Aromatic heterocyclic cyclohexyl amino alkyl piperidine derivative as well as preparation method and application thereof

Abstract

The invention provides an aromatic heterocyclic cyclohexyl amino alkyl piperidine derivative, a preparation method and application of the aromatic heterocyclic cyclohexyl amino alkyl piperidine derivative. Specifically, provided are a compound of formula (I), a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, and a preparation method thereof, which is used for activating the activity of a 5-HT1A receptor and dopamine D2 and D3 receptors, and a use in the preparation of drugs for treating Parkinson's disease. # imgabs0 #

Description

Aromatic heterocyclic cyclohexylaminoalkylpiperidine derivative, preparation method and use thereof

[0001] This application claims priority to Chinese Patent Application No. 2022109619064, filed on August 11, 2022. This application incorporates the entirety of the aforementioned Chinese Patent Application. Technical Field

[0002] The present invention belongs to the field of medicine and specifically relates to an aromatic heterocyclic cyclohexylaminoalkylpiperidine derivative, a preparation method, and its use. More specifically, the present invention relates to an aromatic heterocyclic cyclohexylaminoalkylpiperidine derivative, a preparation method, a pharmaceutical composition containing the aromatic heterocyclic cyclohexylaminoalkylpiperidine derivative, and the use of the aromatic heterocyclic cyclohexylaminoalkylpiperidine derivative or its pharmaceutical composition in the preparation of a medicament for preventing and / or treating diseases of the central nervous system of a mammal. Background Art

[0003] Parkinson's disease (PD) is the second most common neurodegenerative disease in the world after Alzheimer's disease. It often occurs in the elderly, with a prevalence of approximately 2% in people over 60 years old (Lilienfeld, DE Neuroepidemiology, 1993, 12, 219–228.). Its clinical characteristics are mainly manifested as resting tremor, muscle rigidity, bradykinesia and postural balance disorders (Armstrong MJ. JAMA. 2020; 323(6): 548–560.), and may be accompanied by non-motor symptoms such as autonomic nervous system disorders (Jost WH. J Neurol. 2003 Feb; 250 Suppl 1: I28-30.), cognitive impairment (Halliday, GMMov. Disord. 2014, 29, 634–650.), sleep disorders and mood disorders (Gallagher, DA Neurobiol. Dis. 2012, 46, 581–589.). Pathologically, degeneration of dopamine neurons in the substantia nigra pars compacta leads to a significant decrease in dopamine levels in the striatum, and the accumulation of α-synaptophysin, forming Lewy bodies (Schapira, AH Neurol. Clin. 2009, 27, 583–603), which in turn contributes to various movement disorders. Non-motor disorders, in addition to being affected by the dopamine pathway, are also associated with degeneration of other neural pathways, including cholinergic, noradrenergic, and serotonergic (Titova N. Med J Aust 2018; 208:404-409) (Titova NJ Neural Transm (Vienna) 2017; 124:907-914).

[0004] Currently, drug treatment for Parkinson's disease mainly focuses on dopamine strategies, including levodopa (L-DOPA), monoamine oxidase B inhibitors (MAOIs), catechol-O-methyltransferase inhibitors (COMTIs), and dopamine agonists (DAs). L-DOPA has long been the most commonly used drug for Parkinson's disease and remains the gold standard for treating Parkinson's disease. MAOIs and COMTIs are often used as adjuncts to levodopa, prolonging its efficacy by blocking dopamine metabolism (Jankovic J. Journal of Neurology, Neurosurgery & Psychiatry 2020; 91: 795-808.)(Armstrong MJ. JAMA. 2020; 323(6): 548–560.). Despite its obvious benefits for symptomatic treatment, long-term use of levodopa often leads to motor fluctuations (on-off phenomenon) and movement disorders (Marsden, CD Lancét 1976, 307, 292-296.).

[0005] Dopamine agonists directly stimulate D2-like receptors (D2, D3, and D4) or D1 receptors to improve motor symptoms (Hisahara S. Int J Med Chem. 2011; 2011: 403039.). Although less effective than levodopa, dopamine agonists alone can adequately control motor symptoms in the early stages of Parkinson's disease, and therefore most patients choose dopamine agonists rather than levodopa for their first treatment (Jankovic J. Journal of Neurology, Neurosurgery & Psychiatry 2020; 91: 795-808.). In the later stages of the disease, dopamine agonists are combined with levodopa to reduce "off" time (Marsden, CD Lancét 1976, 307, 292-296.). Dopamine agonists can also alleviate some non-motor symptoms. For example, pramipexole is effective in treating depressive symptoms, while ropinirole has beneficial effects on sleep, anxiety, and depression. Rotigotine has been shown to be effective in improving swallowing dysfunction, while apomorphine is effective for mood, gastrointestinal, and urinary dysfunction (Torti M. Drugs. 2019 May; 79(7): 693-703.).

[0006] 5-HT 1A Receptors also play an important role in Parkinson's disease treatment, mainly in three aspects. First, 5-HT 1AReceptor agonists can improve extrapyramidal disorders caused by dopamine neuron degeneration and dyskinesias caused by levodopa, such as eltoprazine, NLX-112, (Cerri S. Expert Opin Investig Drugs. 2017 Jul; 26(7): 777-791.). Secondly, 5-HT 1A The 5-HT receptor helps improve cognitive impairment and produces anxiolytic and antidepressant effects, such as aripiprazole (Ohno Y. Prog Neurobiol. 2015 Nov; 134: 104-21.). In addition, various models have shown that 5-HT 1A Receptor agonists can prevent neurotoxicity, which means that the disease progression can be controlled by protecting neurons from damage, such as BAY-639044. Miyazaki et al. showed that 5-HT 1A Activation of the receptor can induce astrocyte proliferation and increase the level of antioxidant molecules in the striatum, thereby preventing progressive dopaminergic neuron degeneration (Miyazaki I. Curr Med Chem. 2016; 23(7): 686-700.).

[0007] In addition, 5HT has been found in the aqueous humor of the human eye (Martin et al., Ophthalmol., 95: 1221-1226, 1988.). It has been demonstrated in the irido-ciliary body (ICB) of rabbits that [ 3 [H] 5HT receptor binding sites have been identified and pharmacologically characterized (Mallorga and Sugrue, Curr. Eye Res., 6:527-532, 1987 and Chidlow et al., Invest. Ophthalmol. Vis. Sci., 36:2238-2245, 1995.). These 5HT binding sites have been shown to functionally couple second messengers produced by rabbits (Tobin and Osborne, J. Neurochem., 53:686-601, 1989 and Tobin et al., J. Neurosci, supra.). In human ICBs, these binding sites have been characterized as 5HT 1A and 5HT2 receptors (Barnet and Osborne, Exp. Eye Res., 57:209-216, 1993.). In addition, the presence of 5HT in the ICB of rabbits has been reported. 1AmRNAs of receptors (Chidlow et al., Invest. Ophthalmol. Vis. Sci., supra and osborne and Chidlow, Opthalmologica, 210: 308-314, 1996.).

[0008] 8-Hydroxy DPAT and MKC-242 (5HT 1A Studies in rabbits with 5HT agonists have shown that these 1A Agonists can lower IOP (Osborne and Chidlow, Ophthalamologica, 210: 308-319, 1996, EP 0771563A2.). In addition, 5-methylpiperidone (5HT 1A Agonists) can reduce the IOP of monkeys with glaucoma (Wang, et al., Curr. Eye Res., 16:679-775, 1997.). U.S. Patent No. 5693654 discloses 5HT1 receptor agonists for lowering IOP. WO 92 / 20333 discloses certain 5HT1 receptor agonists for treating glaucoma. 1A Agonist.

[0009] Eltoprazine is a 5HT 1A / 1B Agonist (EC 50 =148nM), was granted orphan drug designation by the U.S. FDA in 2016 for the treatment of levodopa-induced dyskinesia (LID). It is currently in Phase II clinical trials and has shown good efficacy and safety in the treatment of cognitive and movement disorders (Cabedo N. Journal of medicinal chemistry, 2001, 44(11):1794-1801.).

[0010] NLX-112 as a selective 5HT 1A Agonist (EC 50 =3.3nM,E max=84%), is being tested for the treatment of levodopa-induced dyskinesia (LID) in Parkinson's disease (PD) and is currently undergoing Phase II clinical trials at Neurolixis. Literature reports (Noureddine El Aouad. European Journal of Medicinal Chemistry, 44(11):4616-4621.) indicate that NLX-112 exhibits novel therapeutic properties, exhibiting significant anti-dyskinesia effects without compromising the therapeutic properties of L-DOPA, and also improving non-motor psychiatric and mood symptoms, such as antidepressant and antianxiety effects.

[0011] In addition, 5-HT 1A Receptor agonists alleviate motor and non-motor disorders primarily through non-dopaminergic mechanisms, meaning a multi-target approach combining the therapeutic effects of both dopaminergic and serotonergic receptors will provide a dual effect in the treatment of Parkinson's disease (Ohno Y. Prog Neurobiol. 2015 Nov; 134: 104-21.)(Shimizu S. Aging Dis. 2013 Feb; 4(1): 1-13.). Currently, molecules with this multi-target feature have demonstrated clinical efficacy.

[0012] SOMCL-171(D2:EC 50 =873nM,E max =74%; 5-HT 1A :EC 50 =175nM,E max =83%) as D2 / 5-HT 1A Agonists exhibit anti-Parkinsonian effects in the 6-OHDA-lesioned rat model and can also slow down the onset of LID (L-DOPA-induced dyskinesia) without diminishing the efficacy of Parkinson's disease (Zhao R, Lu W, Fang X, et al. 2014 Sep; 124: 204-10.).

[0013] Bifeprunox(D2:EC 50 =39.8nM; D3:IC 50 =15.2nM; 5-HT 1A :EC 50 =47.8nM) is an anti-Parkinson's drug under development by Solvay and is currently in Phase III clinical trials. Clinical trials have shown that it can improve motor symptoms and relieve psychiatric symptoms such as depression and anxiety (Wang, Q. Neuropharmacology, 2019, 148:1-10.).

[0014] Pardoprunox(SLV-308)(D2:EC 50 =10nM; D3:EC 50 =0.6nM; 5-HT 1A :EC 50 =500nM) is a D2 / D3 / 5-HT 1A A dopamine agonist with anti-Parkinson's, antidepressant, and antianxiety properties (Jones CA. Eur Neuropsychopharmacol. 2010 Aug; 20(8): 582-93). Furthermore, compared to single-target dopamine agonists, it is less likely to cause side effects such as movement disorders and has entered Phase III clinical trials for the treatment of Parkinson's disease (Glennon, JC Synapse 2006, 60, 599–608).

[0015] In addition, Swati Biswas published a class of 2-aminothiazole derivatives with selective D3 agonist activity in a 2008 article (Biswas SJ Med Chem. 2008; 51(10): 3005-3019.), among which the compounds ((-)31, (-)33) that are relatively close to the compounds of this patent have the following structures:

[0016] The compound has certain D2 and D3 receptor affinity activity and can be used to treat Parkinson's disease. 2L The affinity activity K of D3 receptor binding i The values ​​were 1979±567nm and 44.0±10.6nm, respectively, with a ratio of 58.6; (-)33 vs. D 2L and D3 receptor agonist efficacy EC 50 They were 13.4±2.4 (78.8±0.8%) and 0.06±0.015 (95.7±10.7%) respectively, with a ratio of 223.

[0017] JP2005104885A discloses a novel thiazole derivative that has a strong affinity for dopamine D2 receptors and 5-hydroxytryptamine 5-HT 1A The receptors all showed agonist effects. Among them, the structure of the compound Example 19, which is relatively similar to the compound of this patent, is as follows. The technical effects of this compound are not described in the specification:

[0018] In summary, given that dopamine D2, D3 receptors and / or 5-HT 1A There are multiple receptor targets for synergistic effects, including dopamine D2, D3 receptors and / or 5-HT 1AMulti-target chemical small molecules with receptor activity are expected to play a new role in clinical treatment in treating the main motor symptoms of Parkinson's disease while overcoming movement disorders, improving cognitive impairment, and improving mental and emotional states such as anxiety and depression. In particular, dopamine D2, D3 and / or 5-HT 1A Multi-target agonists have become an important direction for the development of new drugs such as anti-Parkinson's, anti-depression, and anti-schizophrenia drugs worldwide in terms of drug research and development and application. Research in this field is novel, creative, and of great scientific value.

[0019] Summary of the Invention

[0020] The technical problem to be solved by the present invention is to provide an aromatic heterocyclic and cyclohexylaminoalkylpiperidine derivative, a preparation method and its use. In particular, the present invention aims to develop a novel aromatic heterocyclic and cyclohexylaminoalkylpiperidine derivative having D2, D3, 5-HT 1A A new type of anti-Parkinson's disease drug with full receptor agonist effect can effectively treat movement and non-movement disorders and reduce various toxic side effects. It overcomes the main defects of existing drugs, such as poor treatment effect of D2 and D3 dual full agonists on non-movement disorders and the existence of LID side effects, limited effect of selective D3 agonists on Parkinson's movement disorders, and poor anti-Parkinson's efficacy of D2 and D3 dual partial agonists.

[0021] The object of the present invention is to provide a compound represented by general formula (I), its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof,

[0022] in:

[0023] X is selected from amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6- 10 Aryl, 5-10 membered heteroaryl, C 6-10 Aryl C 3-8 Cycloalkyl, C 6-10 Aryl and 3-8 membered heterocyclic group, C 6- 10 aryl and 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl and C 3-8 Cycloalkyl or 5- to 10-membered heteroaryl and 3- to 8-membered heterocyclic group, optionally further substituted by one or more R;

[0024] R is selected from hydrogen, deuterium, halogen, hydroxyl, amino, mercapto, nitro, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6Haloalkoxy, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 The haloalkoxy group is optionally further selected from deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0025] Z is selected from a bond, -(CR aa R bb ) m -、-C(O)(CR aa R bb ) m -、-O(CR aa R bb ) m -、-(CR aa R bb ) m O-、-(CR aa R bb ) m N(R cc )-、-S(O)(CR aa R bb ) m -、-S(O)2(CR aa R bb ) m -、-C(O)(CR aa R bb ) m N(R cc )-、-C(S)(CR aa R bb ) m N(R cc )-or-C(S)(CR aa R bb ) m -;

[0026] M1 and M2 are each independently selected from CR aa , N, O or S;

[0027] R aa and R bb are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, thiol, nitro, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6Haloalkoxy, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 The haloalkoxy group is optionally further selected from deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0028] R cc Selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 The haloalkoxy group is optionally further selected from deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0029] R1 is selected from hydrogen, deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 The haloalkoxy group is optionally further selected from deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0030] R2 is selected from hydroxyl, amino, thiol, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0031] n is selected from 0, 1, 2, 3 or 4;

[0032] m is selected from 0, 1, 2, 3, 4, 5 or 6.

[0033] In a further preferred embodiment of the present invention, the general formula (I) Selected from the following groups: Preferred

[0034] In a further preferred embodiment of the present invention, X is selected from amino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl or C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted by one or more R, preferably amino, C 4-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl, or benzo 5- to 6-membered heteroaryl, optionally further substituted by one or more R.

[0035] In a further preferred embodiment of the present invention, said R is selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy, preferably hydrogen, deuterium, halogen, cyano or C 1-6 Alkyl, more preferably hydrogen, deuterium, fluorine, chlorine, bromine, cyano or C 1-3 The alkyl group is more preferably hydrogen, deuterium, fluorine, chlorine, cyano or methyl.

[0036] In a further preferred embodiment of the present invention, said Z is selected from a bond, -(CH2) m -、-C(O)-、-C(O)(CH2) m -、-S(O)2-、-S(O)2(CH2) m or -C(O)N(CH3)-, preferably a bond, -C(O)-, -S(O)2- or -C(O)N(CH3)-.

[0037] In a further preferred embodiment of the present invention, said R1 is selected from hydrogen, deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 Alkoxy, preferably hydrogen, deuterium or C 1-6 Alkyl, more preferably hydrogen, deuterium or C 1-3The alkyl group is more preferably hydrogen, deuterium, methyl, ethyl or propyl.

[0038] In a further preferred embodiment of the present invention, said R2 is selected from hydroxyl, amino, C 1-6 Alkyl or C 1- 6 haloalkyl, preferably hydroxy, amino, C 1-3 Alkyl or C 1-3 The halogenated alkyl group is more preferably a hydroxyl group or an amino group, and further preferably an amino group.

[0039] In a further preferred embodiment of the present invention, n is selected from 0, 1, 2 or 3, preferably 0, 1 or 2.

[0040] In a further preferred embodiment of the present invention, X is selected from the following groups:

[0041] in:

[0042] o is selected from 0, 1, 2, 3, 4 or 5; and R is as defined above.

[0043] In a further preferred embodiment of the present invention, X is selected from the following groups:

[0044] In a further preferred embodiment of the present invention, the general formula (I) further has a structure represented by the general formula (II):

[0045] in:

[0046] X, Z, R1 and n are as defined above.

[0047] In a further preferred embodiment of the present invention, the general formula (I) further has a structure represented by the general formula (III):

[0048] in:

[0049] Ring A is selected from C 6-10 Aryl, 5-10 membered heteroaryl or C 6-10 Aryl and 5-10 membered heteroaryl, preferably C 6-10 Aryl or benzo 5- to 6-membered heteroaryl, more preferably phenyl or benzothiophenyl;

[0050] R, R1, n and o are as defined above.

[0051] In a further preferred embodiment of the present invention, the general formula (III) Selected from the following groups: Preferred

[0052] in:

[0053] R3 and R4 are each independently selected from halogen, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy, preferably halogen, cyano or C 1-6 The alkyl group is more preferably fluorine, chlorine or bromine, and further preferably chlorine.

[0054] In a further preferred embodiment of the present invention, the general formula (III) Selected from the following groups:

[0055] In a further preferred embodiment of the present invention, the general formula (I) further has a structure represented by the general formula (IV):

[0056] in:

[0057] Xa is selected from amino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with one or more R a Substituted, preferably amino, C 4-6 Cycloalkyl, 4-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with one or more R a replaced by;

[0058] R a Selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy, preferably hydrogen, deuterium, halogen, cyano or C 1-6 Alkyl, more preferably hydrogen, deuterium, fluorine, chlorine, bromine, cyano or C 1-3 Alkyl, further preferably hydrogen, deuterium, fluorine, chlorine, cyano or methyl;

[0059] n1 is selected from 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 1.

[0060] In a further preferred embodiment of the present invention, Xa is selected from the following groups:

[0061] in:

[0062] y is selected from 0, 1, 2 or 3, preferably 0, 1 or 2.

[0063] In a further preferred embodiment of the present invention, Xa is selected from the following groups:

[0064] Wherein: R5 and R6 are independently selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy, preferably halogen, cyano or C 1-6 Alkyl, more preferably fluorine, chlorine, bromine, cyano or C 1-3 The alkyl group is more preferably fluorine, chlorine, cyano or methyl.

[0065] In a further preferred embodiment of the present invention, Xa is selected from the following groups:

[0066] In a further preferred embodiment of the present invention, the compound is selected from:

[0067] The present invention further provides a compound represented by general formula (V), its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof,

[0068] in:

[0069] n1 is selected from 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 1.

[0070] The present invention further provides a method for preparing a compound of formula (IV), its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof, comprising the steps of:

[0071] The compound of general formula (V) undergoes a condensation reaction with a substituted carboxylic acid or an acid chloride to obtain a compound of general formula (IV), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof;

[0072] wherein: n1 and Xa are as described in general formula (IV).

[0073] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the compound represented by the above-mentioned general formula, its stereoisomers, its tautomers or pharmaceutically acceptable salts, and at least one pharmaceutical excipient among pharmaceutically acceptable carriers, diluents or excipients.

[0074] In some embodiments of the present invention, the pharmaceutical composition can be formulated according to any method well known in the art. The carrier refers to a conventional carrier in the pharmaceutical field, such as a filler or binder, such as a cellulose derivative, gelatin, or polyvinyl pyrrolidone; a diluent such as water; an excipient such as starch; a disintegrant such as calcium carbonate or sodium bicarbonate; or a lubricant such as calcium stearate or magnesium stearate. Other adjuvants such as sweeteners, flavoring agents, or colorants may also be added to the composition.

[0075] In some embodiments of the present invention, the pharmaceutical composition can be administered in any of the following ways: oral administration, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal or intracranial injection or infusion, or administration via an explanted reservoir, wherein oral administration is preferred.

[0076] When administered orally, the compounds of the present application can be prepared into any orally acceptable preparation form, including but not limited to tablets, capsules, aqueous solutions or aqueous suspensions.

[0077] The present invention also provides a preferred embodiment, which relates to the use of the compounds represented by the general formulae, their stereoisomers, their tautomers or pharmaceutically acceptable salts, or the pharmaceutical compositions in the preparation of drugs.

[0078] The present invention also provides a preferred embodiment, which relates to the use of the compounds represented by the general formula, their stereoisomers, their tautomers or their pharmaceutically acceptable salts, or the pharmaceutical compositions in the preparation of drugs involving or regulating 5-hydroxytryptamine receptors and / or dopamine receptors, preferably in the preparation of drugs involving or regulating 5-HT 1A receptors, dopamine D2 receptors and / or dopamine D3 receptor drugs.

[0079] The present invention further provides the use of the compounds represented by the above-mentioned general formulas, their stereoisomers, their tautomers or pharmaceutically acceptable salts, or the pharmaceutical compositions in the preparation of drugs for treating central nervous system diseases.

[0080] The present invention further provides the use of the compounds represented by the above-mentioned general formulas, their stereoisomers, their tautomers or pharmaceutically acceptable salts, or the pharmaceutical compositions in the treatment of central nervous system diseases.

[0081] In a preferred embodiment of the present invention, the central nervous system disease is selected from one or more of Parkinson's disease, schizophrenia, bipolar disorder, depression, anxiety, mania, Huntington's disease, Alzheimer's disease, senile dementia, Alzheimer's type dementia, memory impairment, loss of executive function, vascular dementia, neuropathic pain and functional disorders related to intelligence, learning or memory, glaucoma, age-related macular degeneration, optic neuritis, ischemic disorder and retinal edema, more preferably Parkinson's disease.

[0082] Detailed description of the invention

[0083] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0084] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present invention. In certain embodiments, preferred compounds are those isomeric compounds that exhibit superior biological activity. Purified or partially purified isomers and stereoisomers of the compounds of the present invention, or racemic mixtures or diastereomeric mixtures, are also included within the scope of the present invention. Purification and isolation of such substances can be achieved by standard techniques known in the art.

[0085] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0086] Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability to rotate freely about double bonds or single bonds forming ring carbon atoms.

[0087] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0088] The compounds of the present invention may exist in specific forms. Unless otherwise indicated, the term "tautomer" or "tautomeric form" refers to isomers with different functional groups that are in dynamic equilibrium at room temperature and can quickly convert into each other. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur through the reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0089] The term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, which is connected to the rest of the molecule by a single bond. "Alkyl" can have 1 to 8 carbon atoms, i.e., "C1-C8 alkyl", for example, C1-4 alkyl, C1-3 alkyl, C1-2 alkyl, C3 alkyl, C4 alkyl, C1-6 alkyl, C3-6 alkyl. Non-limiting examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or the like, or isomers thereof. The alkyl group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from deuterium, alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, mercapto, hydroxy, nitro, amino, or cyano, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy is optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy.

[0090] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl group contains 3 to 20 carbon atoms, i.e., a "C3-C20 cycloalkyl" group, such as a C3-18 cycloalkyl group, a C3-16 cycloalkyl group, a C3-12 cycloalkyl group, a C3-8 cycloalkyl group, a C3-6 cycloalkyl group, a C3-5 cycloalkyl group, a C3-4 cycloalkyl group, a C4-8 cycloalkyl group, a C4-6 cycloalkyl group, a C5-6 cycloalkyl group, preferably a C3-8 cycloalkyl group, a C3-6 cycloalkyl group, a C3-5 cycloalkyl group, a C3-4 cycloalkyl group. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups. The cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from deuterium, alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, mercapto, hydroxy, nitro, amino or cyano, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy is optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy.

[0091] The term "heterocyclyl" refers to a saturated or unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen and S(O) m (wherein m is an integer from 0 to 2) heteroatoms, excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. That is, "3-20 membered heterocyclyl", such as 3-18 membered heterocyclyl, 3-16 membered heterocyclyl, 3-12 membered heterocyclyl, 3-8 membered heterocyclyl, 3-6 membered heterocyclyl, 3-5 membered heterocyclyl, 3-4 membered heterocyclyl, 4-8 membered heterocyclyl, 4-6 membered heterocyclyl, 5-6 membered heterocyclyl, preferably 3-8 membered heterocyclyl, 3-6 membered heterocyclyl, 3-5 membered heterocyclyl, 3-4 membered heterocyclyl, 4-8 membered heterocyclyl, 4-6 membered heterocyclyl, 5-6 membered heterocyclyl, optionally containing 1-4 heteroatoms, 1-3 heteroatoms or 1-2 heteroatoms, wherein the heteroatoms are optionally N, O, S(O) m(wherein m is an integer from 0 to 2), but excluding the ring portion of -OO-, -OS- or -SS-, preferably a 3- to 8-membered heterocyclic group containing 1 to 4 heteroatoms selected from N, O or S, more preferably a 4- to 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O or S. Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, 1,3-dioxolane, 2,2-difluoro-1,3-dioxolane or azepanyl. Non-limiting examples of polycyclic heterocyclic groups include spirocyclic, fused ring and bridged ring heterocyclic groups. The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from deuterium, alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, mercapto, hydroxy, nitro, amino or cyano, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy is optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy.

[0092] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings which share adjacent pairs of carbon atoms) group having a conjugated electron system, preferably 6- to 10-membered, such as phenyl and naphthyl.

[0093] The aryl group may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, such as an aryl-cycloalkyl, an aryl-heterocyclic, or an aryl-heteroaryl, preferably C 6- 10 Aryl C 3-8 Cycloalkyl, C 6-10 Aryl and 3-8 membered heterocyclic group or C 6-10 Aryl and 5-10 membered heteroaryl, more preferably C 6-10 Aryl and 5-10 membered heteroaryl, further preferably benzo and 5-6 membered heteroaryl, wherein the heterocyclic group is a heterocyclic group containing 1-3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms, and the heteroaryl is a heteroaryl group containing 1-3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms, and its non-limiting examples (wherein the ring connected to the parent structure is an aryl ring) include:

[0094] The aryl, arylcycloalkyl, arylheterocyclyl or arylheteroaryl may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from deuterium, alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, mercapto, hydroxy, nitro, amino or cyano, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy is optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy.

[0095] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably a 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O or S, more preferably a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, or a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, thiadiazole, pyrazinyl, or benzo derivatives thereof, preferably furyl, triazolyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, pyrrolyl, pyridyl, pyrimidyl, thiazolyl or benzo derivatives thereof; more preferably furyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, pyridyl or benzo derivatives thereof. Non-limiting examples thereof include:

[0096] The heteroaryl group may be fused to a heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, such as a heteroaryl-cycloalkyl group, a heteroaryl-heterocyclic group, preferably a 5- to 10-membered heteroaryl-C 3- 8-membered cycloalkyl or 5-10-membered heteroaryl and 3-8-membered heterocyclic group, wherein the heterocyclic group is a heterocyclic group containing 1-4 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms, and the heteroaryl is a heteroaryl group containing 1-4 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms.

[0097] The heteroaryl, heteroarylcycloalkyl or heteroarylheterocyclyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from deuterium, alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, mercapto, hydroxy, nitro, amino or cyano, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy is optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy.

[0098] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above, preferably containing alkoxy groups of 1 to 8 carbon atoms, more preferably alkoxy groups of 1 to 6 carbon atoms, and most preferably alkoxy groups of 1 to 3 carbon atoms. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, substituents are preferably one or more of the following groups independently selected from deuterium, halogen, hydroxyl, amino, mercapto, nitro, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy.

[0099] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above. Non-limiting examples of halomethyl groups include: fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, chlorofluoromethyl, dichloromethyl, bromofluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, bromodifluoromethyl, bromochlorofluoromethyl, dibromofluoromethyl, and the like; preferably fluoromethyl, difluoromethyl, and trifluoromethyl. Non-limiting examples of haloethyl groups include: 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, 2-chloro-2-fluoroethyl, 2,2-dichloroethyl, 2-bromo-2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2-chloro-2-fluoroethyl, 2-bromo-2,2-dichloroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, 1-chloro-1,2,2,2-tetrafluoroethyl, 2-chloro-1,1,2,2-tetrafluoroethyl, 1,2-dichloro-1,2,2-trifluoroethyl, 2-bromo-1,1,2,2-tetrafluoroethyl, and the like; preferably 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, and 2,2-difluoroethyl. The haloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy.

[0100] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above. Non-limiting examples of halomethoxy include: fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, chlorofluoromethoxy, dichloromethoxy, bromofluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy, trichloromethoxy, bromodifluoromethoxy, bromochlorofluoromethoxy, dibromofluoromethoxy, etc.; preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy. Non-limiting examples of haloethoxy include: 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy, 2-chloro-2-fluoroethoxy, 2,2-dichloroethoxy, 2-bromo-2-fluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, 2-bromo-2,2-difluoroethoxy, 2-bromo-2-chloro-2-fluoroethoxy, 2-bromo-2,2-dichloroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, 1-chloro-1,2,2,2-tetrafluoroethoxy, 2-chloro-1,1,2,2-tetrafluoroethoxy, 1,2-dichloro-1,2,2-trifluoroethoxy, 2-bromo-1,1,2,2-tetrafluoroethoxy, etc.; preferably 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy. The haloalkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups independently selected from deuterium, halogen, hydroxyl, amino, mercapto, nitro, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy.

[0101] The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from deuterium, alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, mercapto, hydroxy, nitro, amino or cyano, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy is optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy.

[0102] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein the definition of alkyl is as described above, and it has 2 to 6 (e.g., 2, 3, 4, 5 or 6) carbon atoms (i.e., C2-6 alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Alkynyl can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from deuterium, alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, mercapto, hydroxyl, nitro, amino or cyano, wherein the alkyl, haloalkyl, alkoxy, haloalkoxy is optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxyl, amino, mercapto, nitro, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy.

[0103] "Hydroxy" refers to an -OH group.

[0104] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0105] "Amino" refers to -NH2.

[0106] "Cyano" refers to -CN.

[0107] "Nitro" refers to -NO2.

[0108] "Mercapto" refers to -SH.

[0109] The terms "include," "comprising," "having," "containing," or "involving," and their variations herein, are inclusive or open-ended and do not exclude other unrecited elements or method steps. Those skilled in the art will understand that the above terms, such as "comprising," encompass the meaning of "consisting of."

[0110] The term "one or more" or the similar expression "at least one" may mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.

[0111] When the lower limit and upper limit of a numerical range are disclosed, any value and any included range falling within the range are specifically disclosed. In particular, each range of values ​​disclosed herein should be understood to mean each value and range encompassed within the broader range.

[0112] Herein, "Z" and "-Z-" both represent the same specific group and can be used interchangeably.

[0113] As used herein, the expression mn refers to a range of m to n and subranges consisting of individual values ​​therein and individual values. For example, the expression "C2-C8" or "C2-8" encompasses a range of 2-8 carbon atoms and should be understood to also encompass any subranges and individual values ​​therein, such as C2-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, etc., as well as C2, C3, C4, C5, C6, C7, C8, etc. For example, the expression "C3-C10" or "C3-10" should be understood in a similar manner, e.g., to encompass any subranges and point values ​​contained therein, such as C3-C9, C6-C9, C6-C8, C6-C7, C7-C10, C7-C9, C7-C8, C8-C9, etc., as well as C3, C4, C5, C6, C7, C8, C9, C10, etc. For another example, the expression "C1-C6" or "C1-6" encompasses a range of 1-6 carbon atoms and should be understood to also encompass any subranges and each point value therein, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, etc., as well as C1, C2, C3, C4, C5, C6, etc. For another example, the expression "three to ten yuan" should be understood to include any sub-ranges therein and each point value, such as three to five yuan, three to six yuan, three to seven yuan, three to eight yuan, four to five yuan, four to six yuan, four to seven yuan, four to eight yuan, five to seven yuan, five to eight yuan, six to seven yuan, six to eight yuan, nine to ten yuan, etc., as well as three, four, five, six, seven, eight, nine, ten yuan, etc. Other similar expressions herein should also be understood in a similar manner.

[0114] As used herein, different expressions such as “X is selected from A, B, or C,” “X is selected from A, B, and C,” “X is A, B, or C,” and “X is A, B, and C” all convey the same meaning, that is, X can be any one or more of A, B, and C.

[0115] The expression "-(CY1Y2)n-" used herein means that each Y1 or Y2 connected to C can be the same or different, that is, each Y1 can be a different group, each Y2 can be a different group, each Y1 can also be the same group, and each Y2 can also be the same group.

[0116] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, "cycloalkyl optionally substituted with alkyl" means that alkyl may but need not be present, and the description includes both the case where the cycloalkyl is substituted with alkyl and the case where the cycloalkyl is not substituted with alkyl.

[0117] The terms "substituted" and "substituted" refer to one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom being replaced by a selection from the designated group, provided that the normal valence of the designated atom in the current situation is not exceeded and the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form stable compounds. When a substituent is described as not being present, it is understood that the substituent can be one or more hydrogen atoms, provided that the structure allows the compound to reach a stable state. When each carbon atom in a group is described as optionally substituted by a heteroatom, the proviso is that the normal valence of all atoms in the group in the current situation is not exceeded and a stable compound is formed.

[0118] If a substituent is described as "optionally substituted with," the substituent may be unsubstituted or substituted. If an atom or group is described as being optionally substituted with one or more of the substituents listed, one or more hydrogen atoms on the atom or group may be replaced with independently selected, optional substituents. When a substituent is oxo (i.e., =0), it means that two hydrogen atoms are replaced. Unless otherwise specified, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0119] When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

[0120] When any variable (e.g., R), as well as variables with labels (e.g., R1, R2, R3, R4, R5, R6, R7, etc.) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. For example, if a group is substituted with 0, 1, 2, 3, or 4 R substituents, the group may be optionally substituted with up to four R substituents, and the options for each R substituent at each occurrence are independent of each other.

[0121] The term "pharmaceutically acceptable" refers to a substance that is, within the scope of normal medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit-risk ratio, and effective for its intended use.

[0122] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity.

[0123] The term "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, along with other chemical components, and other components such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0124] The term "pharmaceutically acceptable carrier" refers to substances that are non-irritating to organisms and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0125] The term "administration" or "administering" refers to a method that enables a compound or composition to be delivered to a desired biological site of action. These methods include, but are not limited to, oral or parenteral (including intracerebroventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, and the like. In particular, injection or oral administration.

[0126] As used herein, the term "treating" includes alleviating, alleviating or ameliorating a disease or symptom, preventing other symptoms, ameliorating or preventing the underlying metabolic factors of a symptom, inhibiting a disease or symptom, for example, preventing the disease or symptom from developing, alleviating a disease or symptom, promoting remission of a disease or symptom, or stopping the symptoms of a disease or symptom, and extends to include prevention. "Treatment" also includes achieving a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit refers to the eradication or amelioration of the condition being treated. In addition, a therapeutic benefit is achieved by eradicating or ameliorating one or more physiological signs associated with the underlying disease, and although the patient may still have the underlying disease, an improvement in the patient's disease is observed. A prophylactic benefit refers to the use of a composition by a patient to prevent the risk of a certain disease, or when a patient develops one or more physiological symptoms of a disease, even though the disease has not yet been diagnosed.

[0127] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating or preventing a target disorder, disease, or condition. The term "neuropsychiatric disorder" refers to a general term encompassing neurological and / or psychiatric disorders.

[0128] With respect to a drug, pharmaceutical unit, or active ingredient, the terms "effective amount," "therapeutically effective amount," or "prophylactically effective amount" refer to a sufficient amount of the drug or pharmaceutical agent to achieve the desired effect with acceptable side effects. The determination of an effective amount varies from person to person, depending on the individual's age and general condition, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine testing.

[0129] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" herein include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0130] The following detailed description of the invention is intended to illustrate non-limiting embodiments so that other technical personnel in the art can more fully understand the technical solutions, principles and practical applications of the present invention, so that other technical personnel in the art can modify and implement the present invention in many forms to best adapt it to the requirements of specific uses. Beneficial effects

[0131] The compound of the present invention has a novel structure and can act on 5-HT 1A receptors, dopamine D2 receptors and / or dopamine D3 receptors, and showed certain agonist activity. Some compounds showed 5-HT 1A The compounds have agonist effects on at least two of the following receptors: 5-HT receptor, dopamine D2 receptor and D3 receptor. 1A The triple agonist activity of the compound at the dopamine D2 and D3 receptors indicates that the compound has significant therapeutic effects on central nervous system disorders such as Parkinson's disease and can be used to prepare drugs for treating central nervous system disorders. BRIEF DESCRIPTION OF THE DRAWINGS

[0132] Figure 1: Effects of Example 28 at different concentrations on Tacrine-induced jaw tremor in rats.

[0133] Figure 2: Effects of Example 32 at different concentrations on Tacrine-induced jaw tremor in rats.

[0134] Figure 3: Effects of Example 33 at different concentrations on Tacrine-induced jaw tremor in rats. DETAILED DESCRIPTION

[0135] The embodiments of the present invention will be described in detail below with reference to the examples, but those skilled in the art will appreciate that the following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the invention. Where specific conditions are not specified in the examples, the methods are carried out according to conventional conditions or the conditions recommended by the manufacturer. Where the reagents or instruments used are not specified by manufacturer, they are all conventional products that can be obtained commercially. Unless otherwise specified, the ratios or percentages used herein are by weight.

[0136] Example

[0137] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS).

[0138] NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using an AVANCE III 600 NMR spectrometer. The solvents used were dimethyl sulfoxide (DMSO), deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3), with tetramethylsilane (TMS) as the internal standard.

[0139] Liquid chromatography-mass spectrometry (LC-MS) was performed using a Shimadzu LCMS2020 mass spectrometer, and HPLC was performed using a Shimadzu LC20A liquid chromatograph.

[0140] The thin layer chromatography silica gel plate used was Yantai Jiangyou silica gel plate, the specification used for TLC was 0.2mm±0.03mm, and the specification used for thin layer chromatography separation and purification products was 0.4mm-0.5mm.

[0141] Intermediate 1a

[0142] (S)-N 6 -(piperidin-4-ylmethyl)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine 1a

[0143] Synthesis scheme:

[0144] Step A: Synthesis of (S)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine

[0145] (S)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (0.24 mol, 1 eq) was dissolved in 320 ml of NMP, and bromopropane (0.96 mol, 4 eq) was added and stirred at room temperature for 18 h. After the reaction was complete, the mixture was filtered and the filter cake was washed with an appropriate amount of isopropanol to obtain a white solid, which was then dried in a 70°C forced air drying oven. The dried sample was dissolved in an appropriate amount of water (30 ml), and a 20% aqueous solution of NaOH was added to adjust the pH to 10. The mixture was extracted with dichloromethane (400 mL*3), and the organic layers were combined, dried, and concentrated to obtain (S)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine. ESI-MS[M+H] + :m / z 212.1.

[0146] Step B: Synthesis of (S)-tert-butyl 4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidine-1-carboxylate

[0147] Take (S)-N 6 4-Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (94.6 mmol, 1 eq) and tert-butyl 4-formylpiperidine-1-carboxylate (113.6 mmol, 1.2 eq) were dissolved in 1,2-dichloroethane (150 mL). Three drops of acetic acid were added at -20°C and stirred for 30 minutes. Sodium triacetoxyborohydride (142.0 mmol, 1.5 eq) was then added and stirred at -20°C for 8 hours. Once the starting materials were substantially reacted or byproducts began to form, the reaction was stopped and diluted with ethyl acetate (100 mL). The reaction was quenched by the addition of 10% hydrochloric acid (150 mL) at -20°C, followed by the addition of saturated NaHCO₃ solution (300 mL). The liquid was separated, and the aqueous layer was extracted with dichloromethane (300 ml * 2). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to give (S)-tert-butyl 4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidine-1-carboxylate (15.2 g, 39.3%). ESI-MS [M+H] + :m / z 409.1.

[0148] Step C: Synthesis of (S)-N 6 -(piperidin-4-ylmethyl)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine

[0149] Tert-butyl (S)-4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidine-1-carboxylate (37.3 mmol, 1 eq) was dissolved in 20 ml of methanol. 14 ml (1.5 eq) of 4 M methanolic hydrogen chloride was added and stirred at room temperature for 12 h. After complete reaction, the solvent was removed by concentration under reduced pressure. After addition of 20 ml of water to disperse the sample, the aqueous phase was washed with 50 ml of ethyl acetate and then adjusted to pH 10 with 10% NaOH solution. The aqueous phase was extracted with dichloromethane (100 ml x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield intermediate 1a (8.5 g, 73.9%). ESI-MS [M+H] + :m / z309.1.

[0150] Intermediate 1b

[0151] 2-(4-(5-fluoropyridin-2-yl)-1,9-dioxaspiro[5.5]undec-4-yl)acetaldehyde 1b

[0152] Synthesis scheme:

[0153] Using the synthetic method of intermediate 1a, replace tert-butyl 4-formylpiperidine-1-carboxylate with tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate in step B, and prepare intermediate 1b via steps AC. ESI-MS [M+H] + :m / z 323.1.

[0154] The intermediate tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate is prepared by the following steps:

[0155] Dissolve tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (21.8 mmol, 1 eq) in 100 ml of dichloromethane, add Dedinmas reagent (21.8 mmol, 1 eq), and stir at room temperature for 1.5 h. After the reaction is complete, add 10% aqueous sodium thiosulfate (100 ml) and saturated aqueous sodium bicarbonate (100 ml), and stir at room temperature for 1 h. Separate the layers, extract the aqueous layer with dichloromethane (100 ml x 2), combine the organic layers, wash with saturated aqueous sodium bicarbonate, dry, and concentrate to obtain tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate. ESI-MS [M+H] + :m / z228.1.

[0156] Example 1

[0157] (S)-N 6 -(1-(2,3-dichlorophenyl)piperidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its dihydrochloride

[0158] (S)-N 6 -(1-(2,3-dichlorophenyl)piperidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine synthesis scheme:

[0159] Step A: Synthesis of (S)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine

[0160] The raw materials, 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (45.0 g, 0.266 mol) and L-(+)-tartaric acid (40.0 g, 0.266 mol), were added to a 1000 mL reaction flask. 450 mL of water was added, and the mixture was heated at 80°C with stirring for 1 hour. After cooling to room temperature and stirring for another 2 hours, solids precipitated completely. The solids were filtered and dried to yield 57.0 g of an off-white solid. The dried solids were recrystallized three times with 8 times the volume of water. The recrystallized product was dispersed in 80 mL of water, and 20% sodium hydroxide solution was added. The pH was adjusted to 12. The mixture was stirred at 0-5°C for 2 hours, and then filtered and dried to yield 15.8 g of (S)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (a yield of 62.0%).

[0161] ESI-MS[M+H] + :m / z 170.0.[α] D 20 -94.5°(C=1,MeOH).

[0162] The mother liquor was recovered and D-(-)-tartaric acid was used as a resolving agent to obtain (R)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (ESI-MS[M+H] + :m / z 170.0.[α] D 20 +99.4° (C=1, MeOH).).

[0163] Step B: Synthesis of 1-(2,3-dichlorophenyl)piperidin-4-one

[0164] 1,2-dichloro-3-iodobenzene (22.0 mmol, 1 eq), 4-piperidone glycol acetal (22.0 mmol, 1 eq), Pd2(dba)3 (0.6 mmol, 0.025 eq) and Xantphos (2.2 mmol, 0.1 eq) were dissolved in toluene (60 mL), sodium tert-butoxide (33.0 mmol, 1.5 eq) was added, and after nitrogen displacement, the mixture was heated to 80-110°C and refluxed for 15 h. After the reaction was complete, the mixture was filtered using diatomaceous earth, and the filtrate was evaporated under reduced pressure to remove the solvent to obtain 5.1 g of the crude intermediate (ESI-MS [M+H] + :m / z 288.1. 1 H NMR (400MHz, DMSO) δ7.29(d,J=2.0Hz,1H),7.28(s,1H),7.16(dd,J=5.7,3.9Hz,1H),3.92(s,4H),3.05–3.00(m,4H),1.78(t,J=5.6Hz,4H).)).

[0165] The crude intermediate was dissolved in acetone (60 mL), 6N hydrochloric acid solution (70 mL) was added, and the mixture was stirred at room temperature overnight. After hydrolysis was complete, water was added and organic impurities were removed by extraction with ethyl acetate. The aqueous layer was adjusted to pH = 10 with NaHCO3 and extracted with ethyl acetate (3 × 100 mL). The layers were separated and the organic layer was concentrated. The crude product was purified by silica gel column chromatography to obtain 2.23 g of 1-(2,3-dichlorophenyl)piperidin-4-one, with a yield of 51.6%.

[0166] ESI-MS[M+H] + :m / z 244.0.

[0167] Step C: Synthesis of (S)-N 6 -(1-(2,3-dichlorophenyl)piperidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine

[0168] (S)-4,5,6,7-Tetrahydrobenzo[d]thiazole-2,6-diamine (3.7 mmol, 1 eq) and 1-(2,3-dichlorophenyl)piperidin-4-one (4.1 mmol, 1.1 eq) were dissolved in 1,2-dichloroethane (20 mL). One drop of acetic acid was added under ice-cooling and the mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (5.5 mmol, 1.5 eq) was then added and stirred at room temperature for 8 hours. Once the starting materials were substantially reacted or byproducts began to form, the reaction was stopped and diluted with ethyl acetate (100 mL). The reaction was quenched with 10% hydrochloric acid (10 mL) under ice-cooling, followed by the addition of saturated NaHCO₃ solution (20 mL). After separation, the aqueous phase was extracted with dichloromethane. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the desired product.

[0169] ESI-MS[M+H] + :m / z 397.0.

[0170] Preparation of hydrochloride salt: Synthesis of (S)-N 6 -(1-(2,3-dichlorophenyl)piperidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine dihydrochloride

[0171] Take (S)-N 6 -(1-(2,3-Dichlorophenyl)piperidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was dissolved in ethyl acetate (5-10 mL), and HCl·EA (2M) was added dropwise to adjust the pH to <3. A solid precipitated and stirred at room temperature for 2-5 h. The dihydrochloride salt of the compound was obtained by filtration.

[0172] ESI-MS[M+H] +:m / z 397.0.

[0173] 1 H NMR (400MHz, DMSO) δ9.63 (s, 1H), 9.44 (s, 1H), 9.17 (s, 2H), 7.36 (d, J = 2.0Hz, 1H ),7.36–7.34(m,1H),7.22–7.16(m,1H),3.70(s,1H),3.50–3.44(m,2H),3.41–3. 31(m,2H)3.15–3.04(m,1H),2.87–2.78(m,2H),2.78–2.72(m,1H),2.71–2.67(m, 1H),2.66–2.59(m,1H),2.37–2.16(m,3H),2.05–1.97(m,1H),1.95–1.74(m,2H).

[0174] Example 2

[0175] (S)-N 6 -(1-(2,3-dichlorophenyl)piperidin-4-yl)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride

[0176] (S)-N 6 -(1-(2,3-dichlorophenyl)piperidin-4-yl)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine synthesis scheme:

[0177] Take compound (S)-N 6 1-(2,3-Dichlorophenyl)piperidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (1.26 mmol, 1 eq) and propionaldehyde (1.26 mmol, 1 eq) were dissolved in 1,2-dichloroethane (10 ml). One drop of acetic acid was added under ice-cooling and the mixture was stirred for 30 min. Sodium triacetoxyborohydride (1.9 mmol, 1.5 eq) was then added and stirred at room temperature for 6 h. When the starting materials were substantially reacted or byproducts began to form, the reaction was stopped and diluted with ethyl acetate (20 mL). The reaction was quenched with 10% hydrochloric acid (5 mL) under ice-cooling, followed by the addition of saturated NaHCO₃ solution (10 mL). After separation, the aqueous phase was extracted with dichloromethane. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the desired product.

[0178] ESI-MS[M+H] +:m / z 439.0.

[0179] Preparation of hydrochloride salt: Synthesis of (S)-N 6 -(1-(2,3-dichlorophenyl)piperidin-4-yl)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine hydrochloride

[0180] Take (S)-N 6 -(1-(2,3-dichlorophenyl)piperidin-4-yl)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was dissolved in ethyl acetate (5-10 mL), HCl·EA (2M) was added dropwise to adjust the pH to <3, solid was precipitated, stirred at room temperature for 2-5 h, and filtered to obtain the hydrochloride of the compound.

[0181] ESI-MS[M+H] + :m / z 439.0.

[0182] 1 H NMR (400MHz, DMSO) δ10.66–10.55(m,1H),9.31(s,2H),7.37(d,J=2.3Hz,1H),7.36–7.35(m,1 H),7.23–7.13(m,1H),3.83(s,1H),3.26–3.21(m,4H),3.19–2.89(m,1H),2.84–2.74(m,2H),2 .73–2.60(m,2H),2.52–2.39(m,1H),2.39–2.26(m,1H),2.27–2.16(m,1H),2.12(s,1H),2.09 –2.04(m,1H),2.05–1.98(m,2H),1.93–1.83(m,1H),1.83–1.77(m,2H),0.98(t,J=7.4Hz,3H).

[0183] Example 3

[0184] (S)-N 6 -(1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride

[0185] (S)-N 6 -(1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine synthesis scheme:

[0186] The synthesis method of Example 1 was used to replace 1,2-dichloro-3-iodobenzene in step B with 4-bromobenzo[b]thiophene, and compound (S)-N was prepared through steps AC. 6 -(1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine; then, the synthesis method of Example 2 was used to synthesize the raw material (S)-N 6 -(1-(2,3-dichlorophenyl)piperidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was replaced by (S)-N 6 -(1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was prepared to obtain the target product.

[0187] ESI-MS[M+H] + :m / z 427.0.

[0188] Preparation of hydrochloride salt: Synthesis of (S)-N 6 -(1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine hydrochloride

[0189] Take (S)-N 6 -(1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was dissolved in ethyl acetate (5-10 mL), HCl·EA (2M) was added dropwise to adjust the pH to <3, solid was precipitated, stirred at room temperature for 2-5 h, and filtered to obtain the hydrochloride of the compound.

[0190] ESI-MS[M+H] + :m / z 427.0.

[0191] 1H NMR (600MHz, DMSO) δ10.57(d,J=18.2Hz,1H),9.35(s,2H),7.75(d,J=5.5Hz,1H),7.67(d,J=8.0 Hz,1H),7.51–7.45(m,1H),7.31(t,J=7.8Hz,1H),6.95(d,J=7.6Hz,1H),3.60–3.54(m,3H),3.3 4–3.09(m,3H),3.08–2.91(m,1H),2.91–2.79(m,2H),2.78–2.58(m,2H),2.48–2.42(m,1H),2.3 4–2.28(m,2H),2.22–2.18(m,3H),2.14–2.03(m,1H),1.89–1.80(m,2H),0.97(q,J=7.1Hz,3H).

[0192] Example 4

[0193] (S)-N 6 -((1-(2,3-dichlorophenyl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its dihydrochloride

[0194] (S)-N 6 -((1-(2,3-dichlorophenyl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine synthesis scheme:

[0195] Step A: Synthesis of ethyl 1-(2,3-dichlorophenyl)piperidine-4-carboxylate

[0196] 1,2-Dichloro-3-iodobenzene (44.3 mmol, 1 eq), ethyl 4-piperidinecarboxylate (44.3 mmol, 1 eq), Pd(OAc)2 (1.1 mmol, 0.025 eq), BINAP (4.43 mmol, 0.1 eq), and Cs2CO3 (66.45 mmol, 1.5 eq) were dissolved in toluene (200 mL). After nitrogen displacement, the mixture was heated to 110°C and refluxed for 15 h. After completion of the reaction, the mixture was filtered through celite and the filtrate was concentrated. The crude product was purified by silica gel column chromatography to obtain the intermediate ethyl 1-(2,3-dichlorophenyl)piperidine-4-carboxylate (6.1 g, 45.6%).

[0197] ESI-MS[M+H] + :m / z 302.1.

[0198] 1H NMR (600MHz, DMSO-d6) δ7.33–7.26(m,2H),7.13(dd,J=7.0,2.5Hz,1H),4.10(q,J=7.1Hz,2H),3.27–3. 18(m,3H),2.72(td,J=11.6,2.5Hz,2H),1.98–1.91(m,2H),1.79–1.70(m,2H),1.21(t,J=7.1Hz,3H)).

[0199] Step B: Synthesis of 1-(2,3-dichlorophenyl)piperidine-4-carboxylic acid

[0200] The intermediate 1-(2,3-dichlorophenyl)piperidine-4-carboxylic acid ethyl ester (20.2 mmol, 1 eq) was dissolved in THF:MeOH (1:1, 60 mL) and a solution of LiOH·H2O (30.3 mmol, 1.5 eq) in water (10 mL) was added. The mixture was stirred at room temperature for 18 h. After the reaction was complete, the solvent was evaporated and the solid was dissolved in 10 mL of water. Organic impurities were removed by extraction with ethyl acetate. The aqueous layer was adjusted to pH 2 and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield the intermediate 1-(2,3-dichlorophenyl)piperidine-4-carboxylic acid (5.3 g, 95.8%).

[0201] ESI-MS[M+H] + :m / z 274.1.

[0202] Step C: Synthesis of (S)-N-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-1-(2,3-dichlorophenyl)piperidine-4-carboxamide

[0203] The intermediate product 1-(2,3-dichlorophenyl)piperidine-4-carboxylic acid (10.9 mmol, 1 eq), EDCI (13.1 mmol, 1.2 eq), HObt (13.1 mmol, 1.2 eq), and triethylamine (21.8 mmol, 2 eq) from the previous step were dissolved in dichloromethane (50 mL) and stirred in an ice bath for 20 min. (S)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (21.8 mmol, 2 eq) was added and stirred at room temperature for 4 h. After the reaction was complete, 20 mL of water was added and the mixture was extracted with dichloromethane (30 mL*3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The intermediate (S)-N-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-1-(2,3-dichlorophenyl)piperidine-4-carboxamide (1.5 g, 32.6%) was obtained by column chromatography.

[0204] ESI-MS[M+H]+:m / z 425.2.

[0205] Step D: Synthesis of (S)-N 6 -((1-(2,3-dichlorophenyl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine

[0206] The intermediate (S)-N-(2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)-1-(2,3-dichlorophenyl)piperidine-4-carboxamide (1.8 g, 4.4 mmol) was dissolved in anhydrous THF (30 ml). 1 M BH3·THF (8.7 ml) was added under ice-cooling conditions and stirred at 60°C for 3-5 days. TLC indicated completion of the reaction. The reaction solution was cooled to room temperature, 10 ml of methanol was added at 0°C, and the reaction solution was concentrated. The sample was acidified with 4 M methanolic hydrogen chloride solution and stirred at room temperature for 2 h. The compound was then freed with saturated sodium carbonate solution. The aqueous phase was extracted with dichloromethyl ether. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The desired product was purified by column chromatography.

[0207] ESI-MS[M+H] + :m / z 411.0.

[0208] Preparation of hydrochloride salt: Synthesis of (S)-N 6 -((1-(2,3-dichlorophenyl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine dihydrochloride

[0209] Take (S)-N 6 -((1-(2,3-dichlorophenyl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was dissolved in ethyl acetate (5-10 mL), HCl·EA (2M) was added dropwise to adjust the pH to <3, a solid precipitated, and the mixture was stirred at room temperature for 1-5 h. The dihydrochloride salt of the compound was obtained by filtration.

[0210] ESI-MS[M+H] + :m / z 411.0.

[0211] 1H NMR (400MHz, DMSO) δ8.82(s,1H),8.72(s,1H),7.38–7.34(m,1H),7.33(s,1H),7.20(dd,J=6.8,2.9Hz,1H),6.86(s,2H),3.53–3.48(m,1 H),3.13–2.92(m,3H),2.79–2.65(m,4H),2.65–2.54(m,2H),2.53–2.44(m,2H),2.30–2.20(m,1H),1.94–1.86(m,4H),1.52–1.42(m,2H).

[0212] Example 5

[0213] (S)-N 6 -(2-(1-(2,3-dichlorophenyl)piperidin-4-yl)ethyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its dihydrochloride

[0214] (S)-N 6 -(2-(1-(2,3-dichlorophenyl)piperidin-4-yl)ethyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine synthesis scheme:

[0215] The synthesis method of Example 4 was adopted, and 4-piperidine-carboxylic acid ethyl ester in step A was replaced with 2-(piperidin-4-yl)ethyl acetate, and the target product was prepared through steps AD.

[0216] ESI-MS[M+H] + :m / z 425.0.

[0217] Preparation of hydrochloride salt: Synthesis of (S)-N 6 -(2-(1-(2,3-dichlorophenyl)piperidin-4-yl)ethyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine dihydrochloride

[0218] Take (S)-N 6 -(2-(1-(2,3-dichlorophenyl)piperidin-4-yl)ethyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was dissolved in ethyl acetate (5-10 mL), and HCl·EA (2M) was added dropwise to adjust the pH to <3. A solid precipitated and stirred at room temperature for 1-5 h. The dihydrochloride salt of the compound was obtained by filtration.

[0219] ESI-MS[M+H] + :m / z 425.0.

[0220] 1H NMR(600MHz,DMSO-d6)δ7.33–7.28(m,1H),7.30–7.26(m,1H),7.14(dd,J=7.6,2.0Hz,1H),6.71(s,2H),3.29–3.24(m,3H),2.91–2.88(m,3H),2.67 –2.60(m,2H),2.46–2.43(m,2H),2.09–2.06(m,1H),1.81–1.76(m,2H),1. 72–1.69(m,1H),1.61–1.46(m,3H),1.41–1.30(m,2H),1.29–1.22(m,2H).

[0221] Example 6

[0222] (S)-N 6 -((1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its dihydrochloride

[0223] (S)-N 6 -((1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine synthesis scheme:

[0224] The synthesis method of Example 4 was adopted, 1,2-dichloro-3-iodobenzene in step A was replaced with 4-bromobenzo[b]thiophene, and the target product was prepared through steps AD.

[0225] ESI-MS[M+H] + :m / z 399.0.

[0226] Preparation of hydrochloride salt: Synthesis of (S)-N 6 -((1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine dihydrochloride

[0227] Take (S)-N 6 -((1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was dissolved in ethyl acetate (5-10 mL), and HCl·EA (2M) was added dropwise to adjust the pH to <3. A solid precipitated and stirred at room temperature for 1-5 h. The dihydrochloride salt of the compound was obtained by filtration.

[0228] ESI-MS[M+H] + :m / z 399.0.

[0229] 1 H NMR (400MHz, DMSO) δ9.47(s,1H),9.38(s,2H),9.30(s,1H),7.85–7.65(m,2H),7. 51(s,1H),7.36(t,J=7.9Hz,1H),7.11–7.07(m,1H),3.62–3.53(m,3H),3.53–3.5 0(m,1H),3.50–3.42(m,3H),3.15–3.06(m,1H),2.98–2.78(m,2H),2.77–2.68(m, 1H),2.64–2.57(m,1H),2.38–2.31(m,1H),2.10–2.03(m,4H),1.79–1.53(m,2H).

[0230] Example 7

[0231] (S)-N 6 -((1-(2,3-dichlorophenyl)piperidin-4-yl)methyl)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride

[0232] (S)-N 6 -((1-(2,3-dichlorophenyl)piperidin-4-yl)methyl)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine synthesis scheme:

[0233] Take the target product (S)-N of Example 4 6 -((1-(2,3-dichlorophenyl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (1.6 mmol, 1 eq) and propionaldehyde (1.6 mmol, 1 eq) were used as raw materials and the target product was prepared by the synthesis method of Example 2.

[0234] ESI-MS[M+H] + :m / z 453.1.

[0235] Preparation of hydrochloride salt: Synthesis of (S)-N 6 -((1-(2,3-dichlorophenyl)piperidin-4-yl)methyl)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine hydrochloride

[0236] Take (S)-N 6 -((1-(2,3-dichlorophenyl)piperidin-4-yl)methyl)-N 6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was dissolved in ethyl acetate (5-10 mL), HCl·EA (2M) was added dropwise to adjust the pH to <3, solid was precipitated, stirred at room temperature for 1-5 h, and filtered to obtain the hydrochloride salt of the compound.

[0237] ESI-MS[M+H] + :m / z 453.1.

[0238] 1 H NMR (400MHz, DMSO) δ10.56(s,1H),9.81–9.24(m,2H),7.38–7.30(m,2H),7.18(dd,J=7.1,2.6Hz,1H),3.36–3.22(m,3H),3.17–3.12(m,2 H),3.09–2.81(m,2H),2.80–2.58(m,4H),2.49–2.38(m,1H),2.32–2.13(m,1H),2.13–1.79(m,6H),1.63–1.30(m,3H),1.01–0.91(m,3H).

[0239] Example 8

[0240] (S)-N 6 -(2-(1-(2,3-dichlorophenyl)piperidin-4-yl)ethyl)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride

[0241] (S)-N 6 -(2-(1-(2,3-dichlorophenyl)piperidin-4-yl)ethyl)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine synthesis scheme:

[0242] Take the target product (S)-N of Example 5 6 -(2-(1-(2,3-dichlorophenyl)piperidin-4-yl)ethyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (0.5 mmol, 1 eq) and propionaldehyde (0.5 mmol, 1 eq) were used as raw materials and the target product was prepared by the synthesis method of Example 2.

[0243] ESI-MS[M+H] + :m / z 467.3.

[0244] Preparation of hydrochloride salt: Synthesis of (S)-N 6-(2-(1-(2,3-dichlorophenyl)piperidin-4-yl)ethyl)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine hydrochloride

[0245] Take (S)-N 6 -(2-(1-(2,3-dichlorophenyl)piperidin-4-yl)ethyl)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was dissolved in ethyl acetate (5-10 mL), HCl·EA (2M) was added dropwise to adjust the pH to <3, solid was precipitated, stirred at room temperature for 1-5 h, and filtered to obtain the hydrochloride salt of the compound.

[0246] ESI-MS[M+H] + :m / z 467.3.

[0247] 1 H NMR(600MHz, DMSO-d6)9.27–8.86(m,2H),7.33–7.27(m,2H),7.15(dd,J=7.5,2.1Hz,1H),3.62–3 .47(m,2H),3.29(s,1H),3.27(s,1H),3.07–3.01(m,3H),2.76–2.69(m,1H),2.68–2.62(m,2H),2 .61–2.54(m,1H),2.48–2.42(m,2H),2.28–2.23(m,1H),1.95–1.92(m,1H),1.83–1.77(m,2H),1. 72–1.65(m,2H),1.64–1.55(m,2H),1.55–1.50(m,1H),1.42–1.32(m,2H),0.93(t,J=7.4Hz,3H).

[0248] Example 9

[0249] (S)-N 6 -((1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride

[0250] (S)-N 6 -((1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine synthesis scheme:

[0251] Take the target product (S)-N of Example 6 6 -((1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (1.7 mmol, 1 eq) and propionaldehyde (1.7 mmol, 1 eq) were used as raw materials and the target product was prepared using the synthesis method of Example 2.

[0252] ESI-MS[M+H] + :m / z 441.1.

[0253] Preparation of hydrochloride salt: Synthesis of (S)-N 6 -((1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine hydrochloride

[0254] Take (S)-N 6 -((1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was dissolved in ethyl acetate (5-10 mL), HCl·EA (2M) was added dropwise to adjust the pH to <3, solid was precipitated, stirred at room temperature for 1-5 h, and filtered to obtain the hydrochloride salt of the compound.

[0255] ESI-MS[M+H] + :m / z 441.1.

[0256] 1 H NMR (400MHz, DMSO) δ10.15(s,1H),9.30(s,2H),7.77(d,J=5.5Hz,1H),7.69(d,J=8 .2Hz,1H),7.44(s,1H),7.33(t,J=7.9Hz,1H),7.00(s,1H),3.54–3.44(m,3H),3.33 –3.31(m,1H),3.27–3.07(m,5H),2.85–2.81(m,4H),2.77–2.67(m,1H),2.44–2.39( m,2H),2.28–2.16(m,1H),2.08–2.04(m,3H),1.89–1.84(m,2H),1.02–0.94(m,3H).

[0257] Example 10

[0258] (S)-N 6 -(2-(1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)ethyl)-N 6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride

[0259] (S)-N 6 -(2-(1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)ethyl)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine synthesis scheme:

[0260] The synthesis method of Example 4 was used to replace 1,2-dichloro-3-iodobenzene in step A with 4-bromobenzo[b]thiophene, and 4-piperidine-ethyl carboxylate with 2-(piperidin-4-yl)ethyl acetate, and the intermediate (S)-N was prepared through steps AD. 6 -(2-(1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)ethyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine. The intermediate (1.2 mmol, 1 eq) and propionaldehyde (1.2 mmol, 1 eq) were used as raw materials to prepare the target product using the synthesis method of Example 2.

[0261] ESI-MS[M+H] + :m / z 455.1.

[0262] Preparation of hydrochloride salt: Synthesis of (S)-N 6 -(2-(1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)ethyl)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine hydrochloride

[0263] Take (S)-N 6 -(2-(1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)ethyl)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was dissolved in ethyl acetate (5-10 mL), HCl·EA (2M) was added dropwise to adjust the pH to <3, solid was precipitated, stirred at room temperature for 1-5 h, and filtered to obtain the hydrochloride salt of the compound.

[0264] ESI-MS[M+H] + :m / z 455.1.

[0265] 1H NMR(600MHz,DMSO-d6)δ10.66(s,1H),9.30(s,2H),7.74(s,1H),7.69(s,1H),7.46(s,1H),7.31(s,1H),7.02(s,1H),3. 83–3.65(m,2H),3.33–3.21(m,1H),3.19–3.13(m,2H),3.12–3.07(m,1H),3.07–3.01(m,1H),2.93–2.84(m,1H),2.83–2 .75(m,1H),2.75–2.71(m,1H),2.71–2.66(m,1H),2.65–2.62(m,1H),2.62–2.58(m,1H),2.41–2.38(m,1H),2.38–2.33( m,1H),1.99–1.96(m,1H),1.89–1.86(m,1H),1.85–1.80(m,3H),1.80–1.74(m,1H),1.58(m,3H),0.95(t,J=7.3Hz,3H).

[0266] Example 11

[0267] (R)-N 6 -((1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride

[0268] (R)-N 6 -((1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine synthesis scheme:

[0269] The synthesis method of Example 4 was used to replace 1,2-dichloro-3-iodobenzene in step A with 4-bromobenzo[b]thiophene, and (S)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine in step C with (R)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine. The intermediate (R)-N 6 -((1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine. The intermediate (0.75 mmol, 1 eq) and propionaldehyde (0.75 mmol, 1 eq) were used as raw materials to prepare the target product using the synthetic method of Example 2.

[0270] ESI-MS[M+H] + :m / z 441.1.

[0271] Preparation of hydrochloride salt: Synthesis of (R)-N 6 -((1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine hydrochloride

[0272] Take (R)-N 6 -((1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was dissolved in ethyl acetate (5-10 mL), HCl·EA (2M) was added dropwise to adjust the pH to <3, solid was precipitated, stirred at room temperature for 1-5 h, and filtered to obtain the hydrochloride salt of the compound.

[0273] ESI-MS[M+H] + :m / z 441.1.

[0274] 1 H NMR(600MHz,DMSO-d6)δ7.67(d,J=5.5Hz,1H),7.61–7.56(m,1H),7.38(dd,J=5.5,0.8Hz,1H),7.26 (t,J=7.8Hz,1H),6.89(dd,J=7.7,0.9Hz,1H),6.59(s,2H),3.42(d,J=11.5Hz,2H),3.36–3.32(m,1 H),3.32–3.28(m,1H),2.98–2.88(m,1H),2.72–2.65(m,2H),2.58–2.47(m,1H),2.48–2.41(m,3H), 2.41–2.35(m,2H),1.93–1.83(m,3H),1.68–1.59(m,1H),1.45–1.31(m,5H),0.88(t,J=7.3Hz,3H).

[0275] Example 12

[0276] N 6 -((1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride

[0277] N 6-((1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine synthesis scheme:

[0278] The synthesis method of Example 11 was used to replace (R)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine in step C with 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine, and the intermediate N was prepared through steps AD. 6 -((1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine. The intermediate (0.5 mmol, 1 eq) and propionaldehyde (0.5 mmol, 1 eq) were used as raw materials to prepare the target product using the synthesis method of Example 2.

[0279] ESI-MS[M+H] + :m / z 441.1.

[0280] Preparation of hydrochloride: Synthesis of N 6 -((1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine hydrochloride

[0281] Take N 6 -((1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was dissolved in ethyl acetate (5-10 mL), HCl·EA (2M) was added dropwise to adjust the pH to <3, solid was precipitated, stirred at room temperature for 1-5 h, and filtered to obtain the hydrochloride salt of the compound.

[0282] ESI-MS[M+H] + :m / z 441.1.

[0283] 1H NMR (400MHz, DMSO-d6) δ10.25(s,1H),9.28(s,2H),7.73(d,J=5.5Hz,1H),7.65(d,J=7.9Hz,1H), 7.44–7.39(m,1H),7.30(t,J=7.8Hz,1H),6.99–6.95(m,1H),3.50–3.42(m,3H),3.36–3.22(m,1H) ,3.19–3.00(m,4H),2.98–2.77(m,2H),2.77–2.55(m,1H),2.48–2.30(m,1H),2.26–2.13(m,1H),2 .09–1.98(m,3H),1.89–1.74(m,2H),1.67–1.50(m,3H),1.17(t,J=7.1Hz,1H),0.98–0.90(m,3H).

[0284] Example 13

[0285] (S)-N 6 -((1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 -ethyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride

[0286] (S)-N 6 -((1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 -Ethyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine synthesis scheme:

[0287] Take the target product (S)-N of Example 6 6 -((1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (0.25 mmol, 1 eq) and acetaldehyde (0.25 mmol, 1 eq) were used as raw materials and the target product was prepared using the synthesis method of Example 2.

[0288] ESI-MS[M+H] + :m / z 427.0.

[0289] Preparation of hydrochloride salt: Synthesis of (S)-N 6 -((1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 -Ethyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine hydrochloride

[0290] Take (S)-N 6 -((1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 -Ethyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was dissolved in ethyl acetate (5-10 mL), HCl·EA (2 M) was added dropwise to adjust the pH to <3, solid was precipitated, stirred at room temperature for 1-5 h, and filtered to obtain the hydrochloride of the compound.

[0291] ESI-MS[M+H] + :m / z 427.0.

[0292] 1 H NMR (600MHz, DMSO-d6) δ9.62(s,1H),7.72(dd,J=5.5,1.5Hz,1H),7.63(d,J=8.0Hz,1H),7.38(d,J=5.5Hz,1H),7. 29(t,J=7.8Hz,1H),6.93(d,J=7.7Hz,1H),3.80–3.68(m,1H),3.49–3.44(m,3H),3.32–3.20(m,1H),3.11–2.97(m, 3H),2.93–2.81(m,1H),2.77–2.70(m,1H),2.68(s,1H),2.65–2.62(m,1H),2.62–2.59(m,1H),2.41–2.39(m,1H), 2.37–2.33(m,1H),2.15–2.08(m,1H),2.04–1.98(m,1H),1.98–1.94(m,1H),1.60–1.52(m,2H),1.37–1.33(m,3H).

[0293] Example 14

[0294] (S)-N 6 -((1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 -Methyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride

[0295] (S)-N 6 -((1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 -Methyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine synthesis scheme:

[0296] Take the target product (S)-N of Example 6 6-((1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (0.75 mmol, 1 eq) and 37% formaldehyde aqueous solution (1.5 mmol, 2 eq) were dissolved in formic acid solution (6 ml) and refluxed at 90°C for 6 h. After the reaction was complete, the mixture was cooled to room temperature, 10 ml of water was added, and the reaction mixture was adjusted to neutral with saturated Na2CO3, followed by extraction with ethyl acetate (10 ml*2). The combined organic layers were washed with saturated brine, dried, concentrated, and purified by column chromatography to obtain the desired product.

[0297] ESI-MS[M+H] + :m / z 413.0.

[0298] Preparation of hydrochloride salt: Synthesis of (S)-N 6 -((1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 -Methyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine hydrochloride

[0299] Take (S)-N 6 -((1-(Benzo[b]thiophen-4-yl)piperidin-4-yl)methyl)-N 6 -Methyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was dissolved in ethyl acetate (5-10 mL), HCl·EA (2M) was added dropwise to adjust the pH to <3, solid was precipitated, stirred at room temperature for 1-5 h, and filtered to obtain the hydrochloride of the compound.

[0300] ESI-MS[M+H] + :m / z 413.0.

[0301] 1 H NMR(600MHz,DMSO-d6)δ10.60(s,1H),9.34(s,2H),7.75(d,J=5.3Hz,1H),7.70–7.67(m,1H ),7.46–7.43(m,1H),7.32(t,J=8.0Hz,1H),7.03–7.00(m,1H),3.50–3.46(m,6H),3.28–3. 25(m,1H),3.17–2.96(m,1H),2.93–2.86(m,1H),2.86–2.81(m,4H),2.76–2.69(m,1H),2.6 7–2.57(m,1H),2.26–2.19(m,1H),2.09–2.06(m,1H),2.00–1.90(m,2H),1.62–1.59(m,2H).

[0302] Example 15

[0303] (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(3-chloro-4-fluorophenyl)methanone and its hydrochloride

[0304] (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(3-chloro-4-fluorophenyl)methanone synthesis scheme:

[0305] 3-Chloro-4-fluorobenzoic acid (2.7 mmol, 1.0 eq), EDCI (3.2 mmol, 1.2 eq), HObt (3.2 mmol, 1.2 eq), and triethylamine (5.4 mmol, 2 eq) were dissolved in dichloromethane (20 mL) and stirred in an ice bath for 20 min. Intermediate 1a (3.2 mmol, 1.2 eq) was added and allowed to react at room temperature for 1.5 h. After the reaction was complete, 20 mL of water was added and the mixture was extracted with dichloromethane (30 mL x 3). The organic layer was washed with water and saturated brine, dried over MgSO4, concentrated, and purified by column chromatography to obtain the desired product. ESI-MS [M+H] + :m / z 465.1.

[0306] Preparation of hydrochloride salt: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(3-chloro-4-fluorophenyl)methanone hydrochloride

[0307] (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(3-chloro-4-fluorophenyl)methanone was dissolved in ethyl acetate (5-10 mL). HCl·EA (2 M) was added dropwise to adjust the pH to <3. A solid precipitated and the mixture was stirred at room temperature for 1-5 h. The hydrochloride of the compound was obtained by filtration.

[0308] ESI-MS[M+H] + :m / z 465.1.

[0309] 1H NMR (600MHz, DMSO-d6) δ10.72(s,1H),9.41(s,2H),7.64–7.60(m,1H),7.54–7.48(m,1H),7.43–7. 39(m,1H),4.45–4.42(m,1H),3.80–3.62(m,2H),3.62–3.42(m,2H),3.40–3.34(m,1H),3.23–3.11( m,2H),3.11–2.98(m,2H),3.00–2.75(m,1H),2.75–2.66(m,1H),2.66–2.55(m,1H),2.53–2.49(m,3 H),2.44–2.31(m,1H),2.23–1.90(m,2H),1.90–1.71(m,1H),1.29–1.19(m,2H),0.94–0.88(m,3H).

[0310] Example 16

[0311] (S)-(4-(2-((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)ethyl)piperidin-1-yl)(3-chloro-4-fluorophenyl)methanone and its hydrochloride

[0312] (S)-(4-(2-((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)ethyl)piperidin-1-yl)(3-chloro-4-fluorophenyl)methanone synthesis scheme:

[0313] 3-Chloro-4-fluorobenzoic acid (1.3 mmol, 1 eq), EDCI (1.6 mmol, 1.2 eq), HObt (1.6 mmol, 1.2 eq), and triethylamine (2.6 mmol, 2 eq) were dissolved in dichloromethane and stirred on ice for 20 min. Intermediate 1b (1.6 mmol, 1.2 eq) was added and allowed to react at room temperature for 1.5 h. Upon completion of the reaction, 20 mL of water was added and the mixture was extracted with dichloromethane (30 mL x 3). The organic layer was washed with water and saturated brine, dried over MgSO4, concentrated, and purified by column chromatography to obtain the desired product.

[0314] ESI-MS[M+H] + :m / z 479.1.

[0315] Preparation of hydrochloride salt: Synthesis of (S)-(4-(2-((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)ethyl)piperidin-1-yl)(3-chloro-4-fluorophenyl)methanone hydrochloride

[0316] (S)-(4-(2-((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)ethyl)piperidin-1-yl)(3-chloro-4-fluorophenyl)methanone was dissolved in ethyl acetate (5-10 mL). HCl·EA (2 M) was added dropwise to adjust the pH to <3. A solid precipitated and the mixture was stirred at room temperature for 1-5 h. The hydrochloride of the compound was obtained by filtration.

[0317] ESI-MS[M+H] + :m / z 479.1.

[0318] 1 H NMR (600MHz, DMSO-d6) δ10.47 (s, 1H), 8.95 (s, 2H), 7.63 (dd, J = 7.2, 2.1Hz, 1H),7.50(t,J=8.9Hz,1H),7.41(ddd,J=8.5,4.7,2.1Hz,1H),4.44–4.41(m,1H),3.69–3.66(m,1 H),3.61–3.44(m,3H),3.26–3.17(m,1H),3.17–3.07(m,1H),3.07–3.04(m,1H),3.04–2.97(m,1H) ,2.90–2.81(m,1H),2.80–2.70(m,1H),2.70–2.65(m,1H),2.65–2.52(m,1H),2.34–2.31(m,1H),1 .98–1.90(m,1H),1.87–1.67(m,5H),1.67–1.53(m,2H),1.33–1.05(m,2H),0.93(t,J=7.3Hz,3H).

[0319] Example 17

[0320] (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(phenyl)methanone and its hydrochloride

[0321] (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(phenyl)methanone synthesis scheme:

[0322] The target product was prepared by adopting the synthesis method of Example 15, replacing the raw material 3-chloro-4-fluorobenzoic acid with benzoic acid.

[0323] ESI-MS[M+H] +:m / z 413.1.

[0324] Preparation of hydrochloride salt: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(phenyl)methanone hydrochloride

[0325] (S)-(4-(((2-Amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(phenyl)methanone was dissolved in ethyl acetate (5-10 mL). HCl·EA (2 M) was added dropwise to adjust the pH to <3. A solid precipitated and the mixture was stirred at room temperature for 1-5 h. The hydrochloride of the compound was obtained by filtration.

[0326] ESI-MS[M+H] + :m / z 413.1.

[0327] 1 H NMR(600MHz,DMSO-d6)δ10.30(s,1H),8.99–8.49(m,2H),7.50–7.42(m,3H),7.40–7.34(m,2H), 4.55–4.39(m,1H),3.70–3.65(m,1H),3.59–3.56(m,1H),3.24–3.15(m,1H),3.14–3.03(m,3H), 3.00–2.72(m,1H),2.72–2.55(m,1H),2.42–2.26(m,1H),2.12–2.09(m,1H),1.99–1.96(m,4H), 1.96–1.89(m,2H),1.87–1.77(m,2H),1.26–1.23(m,1H),1.22–1.20(m,2H),0.95–0.89(m,3H).

[0328] Example 18

[0329] (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(6-chloro-5-fluoropyridin-2-yl)methanone and its hydrochloride

[0330] (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(6-chloro-5-fluoropyridin-2-yl)methanone synthesis scheme:

[0331] The target product was prepared by adopting the synthesis method of Example 15, except that the raw material 3-chloro-4-fluorobenzoic acid was replaced with 2-chloro-3-fluoropyridine-6-carboxylic acid.

[0332] ESI-MS[M+H] + :m / z 466.0.

[0333] Preparation of hydrochloride salt: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(6-chloro-5-fluoropyridin-2-yl)methanone hydrochloride

[0334] (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(6-chloro-5-fluoropyridin-2-yl)methanone was dissolved in ethyl acetate (5-10 mL). HCl·EA (2 M) was added dropwise to adjust the pH to <3. A solid was precipitated. The mixture was stirred at room temperature for 1-5 h and filtered to obtain the hydrochloride salt of the compound.

[0335] ESI-MS[M+H] + :m / z 466.0.

[0336] 1 H NMR (600MHz, DMSO-d6) δ10.21(s,1H),9.07(s,2H),8.07(t,J=8.4Hz,1H),7.67(dd,J=8.4,3.4Hz ,1H),4.45(d,J=12.7Hz,1H),3.69–3.63(m,2H),3.21(s,1H),3.15–3.07(m,4H),3.07–3.02(m,1 H),3.02–2.93(m,1H),2.93–2.74(m,1H),2.70–2.65(m,1H),2.64–2.53(m,1H),2.40–2.27(m,1H ),2.20–2.06(m,1H),2.05–1.89(m,1H),1.90–1.71(m,2H),1.27–1.21(m,4H),0.95–0.88(m,3H).

[0337] Example 19

[0338] (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(6-fluoropyridin-3-yl)methanone and its hydrochloride

[0339] (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(6-fluoropyridin-3-yl)methanone synthesis scheme:

[0340] 6-Fluoronicotinic acid (2.7 mmol, 1 eq), EDCI (3.2 mmol, 1.2 eq), HObt (3.2 mmol, 1.2 eq), triethylamine (5.4 mmol, 2 eq), and intermediate 1a (3.2 mmol, 1.2 eq) were dissolved in DMF and reacted at -10°C for 5 h. After the reaction was complete, 20 mL of water was added and the mixture was extracted with dichloromethane (30 mL x 3). The organic layer was washed with water and saturated brine, dried over MgSO₄, concentrated, and purified by column chromatography to obtain the desired product.

[0341] ESI-MS[M+H] + :m / z 432.1.

[0342] Preparation of hydrochloride salt: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(6-fluoropyridin-3-yl)methanone hydrochloride

[0343] (S)-(4-(((2-Amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(6-fluoropyridin-3-yl)methanone was dissolved in ethyl acetate (5-10 mL). HCl·EA (2 M) was added dropwise to adjust the pH to <3. A solid precipitated and the mixture was stirred at room temperature for 1-5 h. The hydrochloride of the compound was obtained by filtration.

[0344] ESI-MS[M+H] + :m / z 432.1.

[0345] 1H NMR (600MHz, DMSO-d6) δ10.61(s,1H),9.31(s,2H),8.30(d,J=2.4Hz,1H),8.03(td,J=8 .2,2.4Hz,1H),7.29(dt,J=8.6,2.1Hz,1H),4.61–4.34(m,1H),3.68–3.65(m,3H),3.62– 3.46(m,6H),3.13–3.03(m,3H),3.00–2.75(m,1H),2.72–2.57(m,1H),2.43–2.30(m,1H ),2.18–2.06(m,2H),2.04–1.72(m,1H),1.29–1.18(m,3H),0.91(td,J=7.3,2.7Hz,3H).

[0346] Example 20

[0347] (S)-5-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidine-1-carbonyl)picolinonitrile and its hydrochloride

[0348] (S)-5-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidine-1-carbonyl)picolinonitrile synthesis scheme:

[0349] The target product was prepared by adopting the synthesis method of Example 15, except that the raw material 3-chloro-4-fluorobenzoic acid was replaced with 6-cyanonicotinic acid.

[0350] 6-Cyanonicotinic acid (4.0 mmol, 1 eq), EDCI (4.8 mmol, 1.2 eq), HObt (4.8 mmol, 1.2 eq), triethylamine (8 mmol, 2 eq), and intermediate 1a (4.8 mmol, 1.2 eq) were dissolved in DMF and reacted at -10°C for 4 h. After the reaction was complete, 20 mL of water was added and the mixture was extracted with dichloromethane (30 mL x 3). The organic layer was washed with water and saturated brine, dried over MgSO4, concentrated, and purified by column chromatography to obtain the desired product.

[0351] ESI-MS[M+H] + :m / z 439.1.

[0352] Preparation of hydrochloride salt: Synthesis of (S)-5-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidine-1-carbonyl)picolinonitrile hydrochloride

[0353] (S)-5-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidine-1-carbonyl)picolinonitrile was dissolved in ethyl acetate (5-10 mL). HCl·EA (2 M) was added dropwise to adjust the pH to <3 to precipitate a solid. The mixture was stirred at room temperature for 1-5 h and filtered to obtain the hydrochloride salt of the compound.

[0354] ESI-MS[M+H] + :m / z 439.1.

[0355] 1 H NMR (600MHz, DMSO-d6) δ10.45(s,1H),9.14(s,2H),8.77(d,J=2.1Hz,1H),8.15(dt,J=8.0,1.2Hz,1H) ,8.10–8.05(m,1H),4.50–4.45(m,1H),3.77–3.62(m,1H),3.24–3.16(m,1H),3.16–3.01(m,3H),2.97– 2.94(m,1H),2.87–2.80(m,1H),2.75–2.54(m,1H),2.41–2.33(m,1H),2.21–2.07(m,2H),2.07–1.89( m,1H),1.89–1.71(m,2H),1.34–1.27(m,1H),1.28–1.22(m,5H),1.21–1.15(m,1H),0.95–0.89(m,3H).

[0356] Example 21

[0357] (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(1H-indol-2-yl)methanone and its hydrochloride

[0358] (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(1H-indol-2-yl)methanone synthesis scheme:

[0359] The target product was prepared by adopting the synthesis method of Example 15, except that the raw material 3-chloro-4-fluorobenzoic acid was replaced with 2-indolecarboxylic acid.

[0360] ESI-MS[M+H] + :m / z 452.2.

[0361] Preparation of hydrochloride salt: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(1H-indol-2-yl)methanone hydrochloride

[0362] (S)-(4-(((2-Amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(1H-indol-2-yl)methanone was dissolved in ethyl acetate (5-10 mL). HCl·EA (2 M) was added dropwise to adjust the pH to <3. A solid was precipitated. The mixture was stirred at room temperature for 1-5 h and filtered to obtain the hydrochloride salt of the compound.

[0363] ESI-MS[M+H] + :m / z 452.2.

[0364] 1 H NMR(600MHz,D2O)δ7.75(d,J=8.0Hz,1H),7.56(d,J=8.3Hz,1H),7.36(t,J=7.7Hz,1H),7.21(t,J=7.5Hz ,1H),6.94(s,1H),4.83–4.82(m,1H),4.82–4.79(m,3H),4.76–4.74(m,1H),4.52(d,J=13.2Hz,2H),3.84 –3.81(m,1H),3.41–3.27(m,1H),3.28–3.04(m,1H),3.02–2.97(m,1H),2.86–2.83(m,1H),2.78–2.73(m ,1H),2.39–2.13(m,2H),2.04–1.87(m,3H),1.82–1.75(m,2H),1.43–1.29(m,2H),1.00(t,J=7.3Hz,3H).

[0365] Example 22

[0366] (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(benzo[b]thiophen-2-yl)methanone and its hydrochloride

[0367] (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(benzo[b]thiophen-2-yl)methanone synthesis scheme:

[0368] The target product was prepared by adopting the synthesis method of Example 15, except that the raw material 3-chloro-4-fluorobenzoic acid was replaced with benzothiophene-2-carboxylic acid.

[0369] ESI-MS[M+H] + :m / z 469.1.

[0370] Preparation of hydrochloride salt: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(benzo[b]thiophen-2-yl)methanone hydrochloride

[0371] (S)-(4-(((2-Amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(benzo[b]thiophen-2-yl)methanone was dissolved in ethyl acetate (5-10 mL). HCl·EA (2 M) was added dropwise to adjust the pH to <3. A solid was precipitated. The mixture was stirred at room temperature for 1-5 h and filtered to obtain the hydrochloride salt of the compound.

[0372] ESI-MS[M+H] + :m / z 469.1.

[0373] 1 H NMR(600MHz,DMSO-d6)δ10.21(s,1H),9.06(s,2H),8.05–8.00(m,1H),7.96–7.91(m,1H),7.70 (s,1H),7.49–7.42(m,2H),4.42–4.24(m,3H),3.71–3.66(m,1H),3.33–3.15(m,1H),3.14–3.05 (m,4H),3.01–2.96(m,1H),2.92–2.79(m,1H),2.73–2.55(m,1H),2.41–2.30(m,1H),2.23–2.0 7(m,2H),2.05–1.89(m,2H),1.87–1.72(m,2H),1.31–1.22(m,3H),0.92(td,J=7.3,2.4Hz,3H).

[0374] Example 23

[0375] (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(naphthalen-2-yl)methanone and its hydrochloride

[0376] (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(naphthalen-2-yl)methanone synthesis scheme:

[0377] The target product was prepared by adopting the synthesis method of Example 15, replacing the raw material 3-chloro-4-fluorobenzoic acid with 2-naphthoic acid.

[0378] ESI-MS[M+H] + :m / z 463.2.

[0379] Preparation of hydrochloride salt: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(naphthalen-2-yl)methanone hydrochloride

[0380] (S)-(4-(((2-Amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(naphthalen-2-yl)methanone was dissolved in ethyl acetate (5-10 mL). HCl·EA (2 M) was added dropwise to adjust the pH to <3. A solid precipitated and the mixture was stirred at room temperature for 1-5 h. The hydrochloride of the compound was obtained by filtration.

[0381] ESI-MS[M+H] + :m / z 463.2.

[0382] 1 H NMR (600MHz, DMSO-d6) δ10.45(s,1H),9.27(s,2H),8.00–7.98(m,3H),7.95(d,J=1.6Hz,1H),7.61–7.58 (m,2H),7.49(dd,J=8.4,1.7Hz,1H),4.63–4.42(m,1H),3.76–3.61(m,3H),3.43–3.37(m,3H),3.22–3.19 (m,1H),3.12–3.06(m,4H),2.99–2.96(m,1H),2.90–2.80(m,1H),2.77–2.54(m,1H),2.45–2.26(m,1H), 2.23–2.07(m,1H),2.08–1.89(m,1H),1.89–1.71(m,1H),1.39–1.19(m,3H),0.92(td,J=7.3,2.6Hz,3H).

[0383] Example 24

[0384] (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(thiophen-2-yl)methanone and its hydrochloride

[0385] (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(thiophen-2-yl)methanone synthesis scheme:

[0386] The target product was prepared by adopting the synthesis method of Example 15, replacing the raw material 3-chloro-4-fluorobenzoic acid with 2-thiophenecarboxylic acid.

[0387] ESI-MS[M+H] + :m / z 419.1.

[0388] Preparation of hydrochloride salt: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(thiophen-2-yl)methanone hydrochloride

[0389] (S)-(4-(((2-Amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(thiophen-2-yl)methanone was dissolved in ethyl acetate (5-10 mL). HCl·EA (2 M) was added dropwise to adjust the pH to <3. A solid precipitated and the mixture was stirred at room temperature for 1-5 h. The hydrochloride of the compound was obtained by filtration.

[0390] ESI-MS[M+H] + :m / z 419.1.

[0391] 1 H NMR (400MHz, DMSO) δ9.97 (s, 1H), 8.93 (s, 2H), 7.79 (dd, J=5.0, 1.1Hz, 1H), 7.41 (dd, J= 3.7,1.2Hz,1H),7.20–7.14(m,1H),4.39–4.21(m,2H),3.79–3.64(m,1H),3.33–3.19(m, 3H),3.18–3.05(m,4H),3.05–2.97(m,2H),2.94–2.56(m,1H),2.15–2.07(m,2H),1.99–1 .92(m,2H),1.84–1.78(m,2H),1.33–1.27(m,1H),1.27–1.23(m,2H),0.99–0.92(m,3H).

[0392] Example 25

[0393] (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(furan-2-yl)methanone and its hydrochloride

[0394] (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(furan-2-yl)methanone synthesis scheme:

[0395] The target product was prepared by adopting the synthesis method of Example 15, replacing the raw material 3-chloro-4-fluorobenzoic acid with 2-furancarboxylic acid.

[0396] ESI-MS[M+H] + :m / z 403.0.

[0397] Preparation of hydrochloride salt: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(furan-2-yl)methanone hydrochloride

[0398] (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(furan-2-yl)methanone was dissolved in ethyl acetate (5-10 mL). HCl·EA (2 M) was added dropwise to adjust the pH to <3. A solid precipitated and the mixture was stirred at room temperature for 1-5 h. The hydrochloride of the compound was obtained by filtration.

[0399] ESI-MS[M+H] + :m / z 403.0.

[0400] 1H NMR(600MHz,DMSO-d6)δ9.95(s,1H),7.84(d,J=1.6Hz,1H),6.96(d,J=3.4Hz,1H),6.63(dt,J=3.0,1.2Hz,1H),4.35 –4.32(m,2H),3.76–3.63(m,1H),3.23–3.18(m,1H),3.16–3.02(m,1H),3.01–2.94(m,1H),2.90–2.78(m,1H),2.70– 2.65(m,1H),2.65–2.54(m,1H),2.42–2.32(m,1H),2.30–2.27(m,1H),2.12–2.10(m,2H),2.10–2.04(m,1H),1.97–1 .94(m,1H),1.94–1.89(m,1H),1.83–1.78(m,2H),1.78–1.75(m,1H),1.26–1.20(m,3H),0.93(td,J=7.3,2.3Hz,3H).

[0401] Example 26

[0402] (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(1H-pyrrol-2-yl)methanone and its hydrochloride

[0403] (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(1H-pyrrol-2-yl)methanone synthesis scheme:

[0404] The target product was prepared by adopting the synthesis method of Example 15, except that the raw material 3-chloro-4-fluorobenzoic acid was replaced with 2-pyrrolecarboxylic acid.

[0405] ESI-MS[M+H] + :m / z 402.0.

[0406] Preparation of hydrochloride salt: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(1H-pyrrol-2-yl)methanone hydrochloride

[0407] (S)-(4-(((2-Amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(1H-pyrrol-2-yl)methanone was dissolved in ethyl acetate (5-10 mL). HCl·EA (2 M) was added dropwise to adjust the pH to <3. A solid was precipitated. The mixture was stirred at room temperature for 1-5 h and filtered to obtain the hydrochloride salt of the compound.

[0408] ESI-MS[M+H] + :m / z 402.0.

[0409] 1 H NMR(600MHz,DMSO-d6)δ11.41(s,1H),10.11(s,1H),8.86(s,2H),6.90–6.85(m,1H),6.48–6.44(m,1H), 6.14–6.10(m,1H),4.45–4.40(m,2H),3.71–3.67(m,1H),3.24–3.17(m,1H),3.14–3.06(m,2H),3.01–2.9 4(m,2H),2.91–2.79(m,1H),2.71–2.65(m,1H),2.64–2.53(m,1H),2.39–2.29(m,1H),2.13–2.05(m,2H), 2.02–1.90(m,2H),1.88–1.70(m,3H),1.27–1.19(m,2H),1.19–1.14(m,1H),0.93(td,J=7.3,2.2Hz,3H).

[0410] Example 27

[0411] (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(thiazol-5-yl)methanone and its hydrochloride

[0412] (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(thiazol-5-yl)methanone synthesis scheme:

[0413] The target product was prepared by adopting the synthesis method of Example 15, replacing the raw material 3-chloro-4-fluorobenzoic acid with 5-thiazolecarboxylic acid.

[0414] ESI-MS[M+H] + :m / z 420.1.

[0415] Preparation of hydrochloride salt: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(thiazol-5-yl)methanone hydrochloride

[0416] (S)-(4-(((2-Amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(thiazol-5-yl)methanone was dissolved in ethyl acetate (5-10 mL). HCl·EA (2 M) was added dropwise to adjust the pH to <3. A solid precipitated and the mixture was stirred at room temperature for 1-5 h. The hydrochloride of the compound was obtained by filtration.

[0417] ESI-MS[M+H] + :m / z 420.1.

[0418] 1 H NMR(600MHz,DMSO-d6)δ10.49(s,1H),9.45–9.38(m,2H),9.24(s,1H),8.17(s,1H),4.43 –4.40(m,1H),3.46–3.42(m,1H),3.23–3.17(m,1H),3.16–3.03(m,3H),3.01–2.93(m,1H ),2.93–2.80(m,1H),2.74–2.67(m,1H),2.66–2.58(m,1H),2.42–2.34(m,1H),2.21–2.1 0(m,2H),2.05–1.88(m,2H),1.88–1.75(m,2H),1.30–1.20(m,5H),0.92(t,J=7.4Hz,3H).

[0419] Example 28

[0420] (S)-(4-(((2-Amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(1-methyl-1H-pyrazol-4-yl)methanone

[0421] (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(1-methyl-1H-pyrazol-4-yl)methanone synthesis scheme:

[0422] The target product was prepared by adopting the synthesis method of Example 15, except that the raw material 3-chloro-4-fluorobenzoic acid was replaced with 1-methylpyrazole-4-carboxylic acid.

[0423] 1-Methylpyrazole-4-carboxylic acid (2.7 mmol, 1 eq), EDCI (3.2 mmol, 1.2 eq), HObt (3.2 mmol, 1.2 eq), triethylamine (5.4 mmol, 2 eq), and intermediate 1a (3.2 mmol, 1.2 eq) were dissolved in DMF and reacted at -10°C for 8 h. After the reaction was complete, 20 mL of water was added and the mixture was extracted with dichloromethane (30 mL x 3). The organic layer was washed with water and saturated brine, dried over MgSO4, concentrated, and purified by column chromatography to obtain the desired product.

[0424] ESI-MS[M+H] + :m / z 417.1.

[0425] 1 H NMR (600MHz, CDCl3) δ7.58(s,1H),7.50(s,1H),4.53(s,2H),3.82(s,3H),3.79–3.67(m,1 H),2.93–2.85(m,1H),2.64–2.57(m,1H),2.55–2.50(m,1H),2.50–2.37(m,2H),2.37–2.3 0(m,2H),2.29–2.24(m,1H),2.24–2.16(m,1H),1.87–1.82(m,1H),1.81–1.73(m,2H),1.6 2–1.52(m,2H),1.37–1.28(m,3H),1.16(s,2H),1.02–0.99(m,2H),0.78(t,J=7.3Hz,3H).

[0426] Example 29

[0427] (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(cyclohexyl)methanone and its hydrochloride

[0428] (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(cyclohexyl)methanone synthesis scheme:

[0429] The target product was prepared by adopting the synthesis method of Example 15, replacing the raw material 3-chloro-4-fluorobenzoic acid with cyclohexylcarboxylic acid.

[0430] ESI-MS[M+H] + :m / z 419.2.

[0431] Preparation of hydrochloride salt: Synthesis of (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(cyclohexyl)methanone hydrochloride

[0432] (S)-(4-(((2-Amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(cyclohexyl)methanone was dissolved in ethyl acetate (5-10 mL). HCl·EA (2 M) was added dropwise to adjust the pH to <3 to precipitate a solid. The mixture was stirred at room temperature for 1-5 h and filtered to obtain the hydrochloride salt of the compound.

[0433] ESI-MS[M+H] + :m / z 419.2.

[0434] 1 H NMR(600MHz,DMSO-d6)δ10.45(s,1H),9.30(s,2H),4.47–4.30(m,1H),4.03–3.85(m,1H),3.58–3.44(m,5 H),3.18–3.15(m,1H),3.12–3.03(m,2H),3.02–2.76(m,1H),2.72–2.66(m,1H),2.65–2.53(m,1H),2.49–2 .41(m,1H),2.38–2.32(m,1H),2.19–2.11(m,1H),2.08–1.96(m,1H),1.88–1.79(m,2H),1.74–1.63(m,2H) ,1.63–1.58(m,3H),1.38–1.23(m,5H),1.20–1.07(m,3H),1.03–0.99(m,1H),0.91(td,J=7.3,2.2Hz,3H).

[0435] Example 30

[0436] (S)-N 6 -((1-(phenylsulfonyl)piperidin-4-yl)methyl)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride

[0437] (S)-N 6 -((1-(phenylsulfonyl)piperidin-4-yl)methyl)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine synthesis scheme:

[0438] Intermediate 1a (0.65 mmol, 1 eq) was dissolved in DCM (6 ml). Triethylamine (1.95 mmol, 3 eq), DMAP (2 mg, catalytic amount), and benzenesulfonyl chloride (0.65 mmol, 1 eq) were added under ice-bath conditions. Stirring was continued for 2 h. After the reaction was complete, 10 ml of water was added and the mixture was extracted with dichloromethane (20 mL*3). The organic layer was washed with water and saturated brine, dried over MgSO4, and concentrated. The target product was purified by column chromatography.

[0439] ESI-MS[M+H] + :m / z 449.0.

[0440] Preparation of hydrochloride salt: Synthesis of (S)-N 6 -((1-(phenylsulfonyl)piperidin-4-yl)methyl)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine hydrochloride

[0441] Take (S)-N 6 -((1-(phenylsulfonyl)piperidin-4-yl)methyl)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was dissolved in ethyl acetate (5-10 mL), HCl·EA (2M) was added dropwise to adjust the pH to <3, solid was precipitated, stirred at room temperature for 1-5 h, and filtered to obtain the hydrochloride salt of the compound.

[0442] ESI-MS[M+H] + :m / z 449.0.

[0443] 1 H NMR(600MHz,DMSO-d6)δ10.22(s,1H),9.00(s,2H),7.77–7.71(m,3H),7.66(t,J=7.6Hz ,2H),3.71–3.58(m,3H),3.18–3.09(m,1H),3.05–2.99(m,3H),2.93–2.88(m,1H),2.85– 2.75(m,1H),2.69–2.53(m,1H),2.34–2.25(m,1H),2.20–2.13(m,1H),2.16–2.05(m,1H ),1.96–1.89(m,1H),1.82–1.63(m,4H),1.33–1.19(m,4H),0.87(td,J=7.5,2.1Hz,3H).

[0444] Example 31

[0445] (S)-N 6-((1-((3-chloro-4-fluorophenyl)sulfonyl)piperidin-4-yl)methyl)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and its hydrochloride

[0446] (S)-N 6 -((1-((3-chloro-4-fluorophenyl)sulfonyl)piperidin-4-yl)methyl)-N 6 -Propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine synthesis scheme:

[0447] The target product was prepared by adopting the synthesis method of Example 30, except that the raw material benzenesulfonyl chloride was replaced by 3-chloro-4-fluorobenzenesulfonyl chloride.

[0448] ESI-MS[M+H] + :m / z 501.0.

[0449] Preparation of hydrochloride salt: Synthesis of (S)-N 6 -((1-((3-chloro-4-fluorophenyl)sulfonyl)piperidin-4-yl)methyl)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine hydrochloride

[0450] Take (S)-N 6 -((1-((3-chloro-4-fluorophenyl)sulfonyl)piperidin-4-yl)methyl)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine was dissolved in ethyl acetate (5-10 mL), HCl·EA (2M) was added dropwise to adjust the pH to <3, solid was precipitated, stirred at room temperature for 1-5 h, and filtered to obtain the hydrochloride salt of the compound.

[0451] ESI-MS[M+H] + :m / z 501.0.

[0452] 1H NMR(600MHz,DMSO-d6)δ10.10(s,1H),8.56(s,2H),8.00–7.95(m,1H),7.82–7.77(m,1H),7. 72(t,J=8.8Hz,1H),3.70–3.60(m,4H),3.17–3.11(m,1H),3.10–2.95(m,2H),2.95–2.89(m,1 H),2.85–2.75(m,1H),2.69–2.51(m,1H),2.37–2.15(m,3H),2.14–2.03(m,1H),1.98–1.84( m,2H),1.81–1.78(m,2H),1.75–1.71(m,2H),1.29–1.24(m,2H),0.88(td,J=7.3,2.3Hz,3H).

[0453] Example 32

[0454] (S)-4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)-N,N-dimethylpiperidine-1-carboxamide

[0455] (S)-4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)-N,N-dimethylpiperidine-1-carboxamide synthesis scheme:

[0456] The target product was prepared by adopting the synthetic method of Example 30, replacing the raw material benzenesulfonyl chloride with dimethylaminoformyl chloride.

[0457] ESI-MS[M+H] + :m / z 380.2.

[0458] 1H NMR (600MHz, CDCl3) δ4.80(s,2H),3.60–3.54(m,2H),2.92–2.84(m,1H),2.71(s,6H),2.66–2.56(m,2H),2.55–2.49( m,1H),2.44–2.37(m,1H),2.37–2.27(m,2H),2.27–2.21(m,1H),2.21–2.15(m,1H),1.88–1.81(m,1H),1.77–1.74(m, 1H),1.72–1.66(m,1H),1.61–1.51(m,1H),1.48–1.37(m,1H),1.36–1. 27(m,2H),1.25–1.09(m,2H),1.03–0.92(m,2H),0.78(t,J=7.3Hz,3H).

[0459] Example 33

[0460] (S)-(4-(((2-Amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(morpholino)methanone

[0461] (S)-(4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidin-1-yl)(morpholino)methanone synthesis scheme:

[0462] The target product was prepared by adopting the synthesis method of Example 30, replacing the raw material benzenesulfonyl chloride with 4-morpholinecarbonyl chloride.

[0463] ESI-MS[M+H] + :m / z 422.1.

[0464] 1H NMR (600MHz, CDCl3) δ4.86(s,2H),3.67–3.53(m,8H),3.16–3.13(m,4H),2.91–2.83(m ,1H),2.68–2.62(m,2H),2.62–2.55(m,1H),2.54–2.49(m,1H),2.49–2.37(m,1H),2.3 7–2.27(m,2H),2.27–2.22(m,1H),2.21–2.15(m,1H),1.87–1.81(m,1H),1.74–1.66(m ,2H),1.61–1.51(m,1H),1.36–1.26(m,2H),1.03–0.91(m,2H),0.78(t,J=7.3Hz,3H).

[0465] Comparative Example 1

[0466] (S)-N 6 -(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)-N 6 -propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine hydrochloride

[0467] Synthesis scheme:

[0468] With reference to the literature (Biswas SJ Med Chem. 2008; 51(10): 3005-3019.), Comparative Example 1 was prepared according to the above route.

[0469] The following Comparative Examples 2 and 3 were prepared with reference to Example 30 or Example 19 of JP2005104885A.

[0470] Comparative Example 2

[0471] Methyl 4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidine-1-carboxylate hydrochloride

[0472] Comparative Example 3

[0473] (R)-4-(((2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)methyl)piperidine-1-carboxylic acid methyl ester hydrochloride

[0474] Biological test evaluation

[0475] The following further describes the present invention in conjunction with test examples, but these are not intended to limit the scope of the present invention.

[0476] Test Example 1: In vitro 5HT activity of the compounds of the present invention 1A Receptor function experiments

[0477] 1.1 Experimental Materials

[0478] 1.1.1 Cell Information: HEK293 / 5HT 1A , using 5HT 1A Receptor lentivirus infection HEK293 to construct a stable cell line HEK293 / 5HT 1A , growth medium DMEM, 10% FBS, 0.6ug / mL puro; freezing medium: 70% culture medium, 20% FBS, 10% DMSO.

[0479] 1.1.2 Experimental reagents and consumables

[0480] 1.1.3 Experimental instruments

[0481] 1.2 Experimental methods

[0482] (1) Compound preparation: The test compound and 5HT were diluted to 0.1 mM using stimulation buffer.

[0483] (2) Experimental buffer preparation: Dilute 5× stimulation buffer to 1× with ddH2O, add IBMX to a final concentration of 0.5 mM, mix well and set aside.

[0484] (3) Digest the cells with trypsin, centrifuge after termination, resuspend the cell pellet in 10 mL of preheated HBSS, centrifuge, add 1 mL of stimulation buffer and resuspend, and take 20 μL for cell counting.

[0485] (4) Take an appropriate amount of cell suspension and dilute it to 0.6×10 6 5 μL of cell suspension was added to each well of the cell plate and centrifuged at 1000 rpm for 1 minute.

[0486] (5) Use bravo to dilute and transfer compounds: dilute the compounds 4-fold at 8 points on the compound plate; then use bravo to transfer the entire plate of diluted compounds to a 384 white plate and centrifuge at 1000 rpm for 1 minute.

[0487] (6) The test plate was blocked and incubated at room temperature for 15 minutes.

[0488] (7) Forskolin prepared in DMSO was added using a Tecan D300e. The stock solution was 0.2 mM and the final concentration was 1 μM. The mixture was centrifuged at 1000 rpm for 1 minute.

[0489] (8) Seal the plate and incubate at room temperature for 45 minutes.

[0490] (9) Preparation of cAMP standard curve: Starting at 2848 nM, perform 8-point 4-fold serial dilutions. Add 10 μL to the experimental plate, with the highest concentration being 712 nM.

[0491] (10) Add 5 μL of cAMP-d2 solution (the stock solution was diluted with lysis buffer at a ratio of 1:20) to the experimental plate and centrifuge at 1000 rpm for 1 minute.

[0492] (11) Then, 5 μL of Anti-cAMP-Cryptate solution (the stock solution was diluted with lysis buffer at a ratio of 1:20) was added to the experimental plate and centrifuged at 1000 rpm for 1 minute.

[0493] (12) The test plate was incubated at room temperature for 1 hour and centrifuged at 1000 rpm for 1 minute before reading.

[0494] (13) The plate was read using Envision. The excitation light was 320 nm, and the emission light was 620 nm and 665 nm. The exported data were analyzed and processed to calculate the maximum activation rate E of the compound. max and EC 50 .

[0495] 1.3 Experimental results: See Table 1.

[0496] Table 1 Effects of the compounds of the present invention on 5-HT 1A Receptor function experiment results

[0497] Note: In the above table, a represents the free base form of the compound; the others represent the hydrochloride / dihydrochloride form of the compound.

[0498] 1.4 Experimental Conclusions:

[0499] According to the results in Table 1 above, the compounds of the present invention can act on 5-HT 1A receptors and showed good 5-HT 1A Receptor agonist activity.

[0500] Test Example 2: In vitro dopamine D 2L Receptor function experiments

[0501] 2.1 Experimental Materials

[0502] 2.1.1 Cell Information

[0503] 2.1.2 Experimental reagents and consumables

[0504] 2.1.3 Experimental instruments

[0505] 2.2 Experimental methods

[0506] (1) Compound preparation: Dilute the test compound and dopamine to 200 nM for later use.

[0507] (2) Experimental buffer preparation: Dilute 5× stimulation buffer to 1× with ddH2O, add IBMX to a final concentration of 0.5 mM, mix well and set aside.

[0508] (3) Digest the cells with trypsin, centrifuge after termination, resuspend the cell pellet in 10 mL of preheated HBSS, centrifuge, add 1 mL of stimulation buffer and resuspend, and take 20 μL for cell counting.

[0509] (4) Take an appropriate amount of cell suspension and dilute it to 0.4×10 6 5 μL of cell suspension was added to each well of the cell plate and centrifuged at 1000 rpm for 1 minute.

[0510] (5) Use bravo to dilute and transfer compounds: dilute the compounds 4-fold at 8 points on the compound plate; then use bravo to transfer the entire plate of diluted compounds to a 384 white plate and centrifuge at 1000 rpm for 1 minute.

[0511] (6) The test plate was blocked and incubated at room temperature for 15 minutes.

[0512] (7) Forskolin prepared in DMSO was added using a Tecan D300e. The stock solution was 0.2 mM and the final concentration was 0.25 μM. 25.1 nL of forskolin was added to each well and the cells were centrifuged at 1000 rpm for 1 minute.

[0513] (8) Seal the plate and incubate at room temperature for 45 minutes.

[0514] (9) Preparation of cAMP standard curve: Starting at 2848 nM, perform 8-point 4-fold serial dilutions. Add 10 μL to the experimental plate, with the highest concentration being 712 nM.

[0515] (10) Add 5 μL of cAMP-d2 solution (the stock solution was diluted with lysis buffer at a ratio of 1:20) to the experimental plate and centrifuge at 1000 rpm for 1 minute.

[0516] (11) Then, 5 μL of Anti-cAMP-Cryptate solution (the stock solution was diluted with lysis buffer at a ratio of 1:20) was added to the experimental plate and centrifuged at 1000 rpm for 1 minute.

[0517] (12) The experimental plate was incubated at room temperature for 45 minutes and centrifuged at 1000 rpm for 1 minute before reading.

[0518] (13) The plate was read using Envision. The excitation light was 320 nm, and the emission light was 620 nm and 665 nm. The exported data were analyzed and processed to calculate the maximum activation rate E of the compound. max and EC 50 .

[0519] 2.3 Experimental results: See Table 2.

[0520] Table 2 Results of experimental studies on the effects of the compounds of the present invention on D2 receptor function

[0521] Note: In the above table, a represents the free base form of the compound; the others represent the hydrochloride / dihydrochloride form of the compound.

[0522] 2.4 Experimental Conclusions:

[0523] According to the results in Table 2 above, it can be seen that the compounds of the present invention can act on dopamine D2 receptors and exhibit good dopamine D2 receptor (partial) agonist activity.

[0524] Test Example 3: In vitro dopamine D3 receptor function test of the compound of the present invention

[0525] 3.1 Experimental Materials

[0526] 3.1.1 Cell information: CHO-K1 / D3 / CRE, constructed according to the method of Example 5 of CN114369578A.

[0527] 3.1.2 Experimental reagents and consumables

[0528] 3.1.3 Experimental instruments

[0529] 3.2 Experimental methods

[0530] Day 1: Cell plating

[0531] (1) The cultured cells were digested with trypsin. After the digestion of the culture medium was terminated, the cell suspension was transferred to a centrifuge tube and centrifuged at 750 rpm for 5 minutes.

[0532] (2) Discard the supernatant, resuspend the pellet in an appropriate amount of plating medium, and take 20 μL to count the cells using a cell counter.

[0533] (3) Take an appropriate amount of cell suspension and dilute it to 0.5×10 6 20 μL of cell suspension was added to each well of the cell plate (cell density was 10,000 cells / well).

[0534] (4) The cell plate was cultured overnight in 5% CO2 / 37°C.

[0535] Day 2: Laboratory testing

[0536] (1) The test compound was diluted to 0.2 mM using DMSO, and the reference compound Dopamine was diluted to 0.02 mM.

[0537] (2) Compounds were diluted using Bravo (8 concentration points, 4-fold dilution). The starting concentration of the test compound was 5 μM and the reference compound was 500 nM. 5 μL of the solution was then added to the cell plate. The final concentrations of the test compound and the reference compound were 1 μM and 100 nM, respectively. Positive control wells contained 100 nM Dopamine, and negative control wells contained an equal volume of DMSO.

[0538] (3) Centrifuge at 1000 rpm for 1 minute and incubate at 5% CO2 / 37°C for 30 minutes.

[0539] (4) Use Tecan-D300e to transfer 40 nL of 0.2 mM Forskolin DMSO solution to the cell plate, with a final concentration of 0.4 μM. Blank group: add cells without Forskolin.

[0540] (5) Centrifuge at 1000 rpm for 1 minute and incubate at 5% CO2 / 37°C for 4 hours.

[0541] (6) Remove the lysis buffer 30 minutes in advance, thaw in a water bath, and return to room temperature. Take out an appropriate amount of substrate and dilute it with the lysis buffer at a ratio of 1:50. Mix well and set aside.

[0542] (7) Add 20 μL of detection reagent and centrifuge at 1000 rpm for 1 minute.

[0543] (8) After incubation at room temperature for 3 minutes, the plate was read using Envision. The ultrasensitive chemiluminescence detection program was selected. The exported data was analyzed and processed to calculate the maximum activation rate Emax and EC of the compound. 50 .

[0544] 3.3. Experimental results: see Table 3.

[0545] Table 3 Results of experimental studies on the effects of the compounds of the present invention on D3 receptor function

[0546] Note: In the above table, a represents the free base form of the compound; the others represent the hydrochloride / dihydrochloride form of the compound.

[0547] 3.4 Experimental Conclusions

[0548] According to the results in Table 3 above, it can be seen that the compounds of the present invention can act on dopamine D3 receptors and exhibit good dopamine D3 receptor (partial) agonist activity.

[0549] Test Example 4: In vitro liver microsome experiment of the compound of the present invention

[0550] 4.1 Experimental Purpose

[0551] The first-phase metabolic stability of the compounds of the present invention was evaluated in CD-1 mice, SD rats and human liver microsomes.

[0552] 4.2 Experimental Materials

[0553] 4.2.1 Experimental reagents

[0554] 4.2.2 Experimental instruments

[0555] 4.3 Experimental methods

[0556] (1) Preparation of buffer: Dissolve 73.21 g of potassium phosphate dibasic trihydrate and 10.78 g of potassium dihydrogen phosphate in 4000 mL of ultrapure water. Adjust the pH of the solution to 7.40 ± 0.10 using 10% phosphoric acid or 1 M potassium hydroxide, with a final concentration of 100 mM.

[0557] (2) Solution preparation and dilution: Prepare a 10 mM stock solution of the test compound in dimethyl sulfoxide (DMSO) and store at 4°C. Dilute to a 100 μM working solution with pure acetonitrile before use. Prepare a 10 mM stock solution of the control compound testosterone in DMSO and store at -20°C. Dilute to a 400 μM working solution with pure acetonitrile before use.

[0558] (3) Preparation of stop solution: The stop solution is acetonitrile containing the internal standard buspirone. The prepared stop solution is stored in a refrigerator at 2-8°C.

[0559] (4) Preparation of liver microsome solution: Dilute microsomes from various species (CD-1 mouse, SD rat, and human) to a 20× working solution using 100 mM potassium phosphate buffer. The final concentration of microsomes in the reaction system is 0.5 mg / mL.

[0560] (5) Preparation of the reduced nicotinamide adenine dinucleotide phosphate (NADPH) regeneration system: Weigh appropriate amounts of nicotinamide adenine dinucleotide phosphate (NADP), glucose-6-phosphate (G6P), magnesium chloride (MgCl2), and glucose-6-phosphate dehydrogenase (G6PDH) to prepare stock solutions at concentrations of 65.33 mM, 330 mM, 300 mM, and 250 units / mL, respectively. Add the four stock solutions to an appropriate amount of buffer and gently mix by inverting. The final concentrations in the NADPH regeneration system are: 2.65 mM NADP, 10.2 mM G6P, 6.12 mM MgCl2, and 2.45 units / mL G6PDH.

[0561] (6) Incubation process: Incubation was performed in a 96-well plate. Several incubation plates were prepared and named T0, T5, T10, T20, T40, T60, PB60, and NCF60. The first six plates corresponded to reaction time points of 0, 5, 10, 20, 40, and 60 minutes, respectively. In the NCF60 plate, potassium phosphate buffer was used instead of the NADPH regeneration system solution for incubation for 60 minutes. In the PB60 plate, potassium phosphate buffer was used instead of the liver microsomes for incubation for 60 minutes. All condition samples were in triplicate.

[0562] Add 2 μL of test compound or control compound and 100 μL of microsomal working solution (containing 1 mg / mL liver microsomal protein) to T0, T5, T10, T20, T40, T60 and NCF60 plates, respectively. Add 2 μL of test compound and 100 μL of potassium phosphate buffer to PB60 plates, and then place the above incubation plates in a 37°C water bath for approximately 5 minutes.

[0563] After the preincubation, the T0 sample was first added with 600 μL of stop solution, followed by 98 μL of NADPH regeneration system working solution. The plate was sealed and shaken before processing with subsequent samples. For the NCF60 plate, 98 μL of potassium phosphate buffer was added to each well. For all other plates, 98 μL of NADPH regeneration system working solution was added to each well to initiate the reaction. The final concentrations of the test and control compounds in the reaction system were 1 μM and 4 μM, respectively. The concentration of liver microsomes was 0.5 mg / mL. The final concentrations of DMSO and acetonitrile in the reaction system were 0.01% (v / v) and 0.99% (v / v), respectively.

[0564] After incubation for an appropriate time (e.g., 5, 10, 20, 40, and 60 minutes), 600 μL of stop solution containing an internal standard was added to each well containing the test compound and control compound to terminate the reaction. The plate was sealed, shaken, and centrifuged at 4000 × g for 15 minutes at 4°C. The supernatant was transferred to a 96-well sample receiving plate, diluted with an appropriate amount of purified water, and shaken for LC-MS / MS analysis. Data were processed using Analyst 7.1 (Sciex, Framingham, Massachusetts, USA).

[0565] 4.4 Experimental results: See Table 4.

[0566] Table 4 In vitro liver microsome stability test results

[0567] Note: The clearance classification standards are shown in the following table:

[0568] 4.5 Experimental Conclusion

[0569] The results in Table 4 above indicate that the compounds of the present invention exhibit moderate clearance rates in liver microsomes of SD rats and CD-1 mice, and low to medium clearance rates in human liver microsomes. Based on the pharmacodynamic activity and pharmacological mechanisms of this series of compounds, a slower metabolic rate is beneficial for the compounds to exert their pharmacodynamic activity. Therefore, the compounds of the present invention exhibit superior metabolic rate.

[0570] Test Example 5: In vitro hERG assay of the compounds of the present invention

[0571] 5.1 Experimental Materials

[0572] 5.1.1 Experimental reagents

[0573] 5.1.2 Experimental instruments

[0574] 5.1.3 Electrophysiological testing solution

[0575] Extracellular solution: 140 mM NaCl, 3.5 mM KCl, 1 mM MgCl2, 2 mM CaCl2, 10 mM Glucose, 10 mM HEPES, 1.25 mM NaH2PO4, NaOH adjusted to pH = 7.4.

[0576] Intracellular solution: 20 mM KCl, 115 mM K-Aspartic, 1 mM MgCl2, 5 mM EGTA, 10 mM HEPES, 2 mM Na2-ATP, KOH adjusted to pH = 7.2.

[0577] 5.2 Patch clamp assay

[0578] Under an inverted microscope, a glass electrode micromanipulator (micromanipulator) is used to bring the recording electrode into contact with the cell. Negative pressure is then applied to promote the formation of a GΩ seal. After the GΩ seal is formed, rapid capacitance compensation is performed. Then, negative pressure is continuously applied to rupture the cell membrane, establishing whole-cell recording mode. Within whole-cell recording mode, slow capacitance compensation is performed and the membrane capacitance and series resistance are recorded.

[0579] The voltage stimulation protocol for hERG potassium currents was as follows: the cell membrane was clamped at -80 mV, followed by a depolarization from -80 mV to +30 mV for 2.5 seconds, followed by a rapid hold at -50 mV for 4 seconds to elicit tail currents in hERG channels. Data were collected repeatedly every 10 seconds. Leakage current was detected at -50 mV.

[0580] A coverslip seeded with cells was placed in the recording chamber of an inverted microscope. Negative controls and test compounds were gravity-perfused from low to high concentrations, allowing rapid exposure to the cells. During recording, a vacuum pump was used to continuously circulate the external fluid. The current measured in each cell's negative control served as its own control group. Each drug concentration was applied for 5 minutes or until the current stabilized. All experiments were performed at room temperature.

[0581] 5.3 Data Analysis

[0582] First, normalize the current after each drug concentration ((Peak tail current compound) / (Peak tail current vehicle)), and then calculate the corresponding inhibition rate (1-(Peak tail current compound) / (Peak tail current vehicle)). Basic statistics are calculated for each concentration, including the mean (Mean), standard deviation (SD), standard error (SE), and number of replicates (n). The dose-dependent curves are fitted using the following equation, and the half-inhibitory concentration (IC) of the test compound is calculated. 50 ): inhibition=1 / (1+(IC 50 / C)^h)

[0583] Where C represents the concentration of the test compound, IC 50 represents the half-inhibitory concentration, and h represents the Hill coefficient. Curve fitting and IC 50 The calculations were performed using GraphPad Prism 5.0 software.

[0584] 5.4 Experimental results: see Table 5.

[0585] Table 5 Experimental results of the inhibitory activity of the compounds of the present invention on hERG potassium channel receptors

[0586] Note: In the above table, a represents the free base form of the compound; the others represent the hydrochloride / dihydrochloride form of the compound.

[0587] 5.5 Experimental Conclusion

[0588] The hERG inhibition test results in Table 5 above show that most of the compounds described in the present invention have weak or essentially no inhibitory activity on hERG potassium channels. 50 The concentrations of the compounds in this invention are all at 20 μM, and their functional activities are more than 1,000 times lower than those of the drug targets. Therefore, the potential risk of cardiac toxicity of the compounds in this invention is extremely low.

[0589] Test Example 6: Effect of the Compound of the Present Invention on Tacrine-Induced Mandibular Tremor in Rats

[0590] 6.1 Experimental plan

[0591] 6.1.1 Experimental Materials

[0592] Test compounds: free bases of Examples 28, 32, and 33 of the present invention, prepared in-house.

[0593] Positive control compound: Rotigotine.

[0594] Modeling drug: Tacrine, SIGMA, A3773-1G.

[0595] Solvent: Normal saline, Chenxin Pharmaceutical Co., Ltd., 2111060723.

[0596] 6.1.2 Experimental instruments

[0597] 6.1.3 Experimental Animals

[0598] Sprague Dawley rats, male, 10 rats / group, obtained from Shanghai Slake Laboratory Animal Co., Ltd.

[0599] 6.1.4 Dosage Information

[0600] Drug preparation: Take the test compound, add the solvent and perform sonication.

[0601] Route and method of administration: Intraperitoneal injection.

[0602] Frequency and duration of administration: Single dose.

[0603] 6.2 Experimental methods

[0604] Rats were randomly divided into a model group, a drug-treated group, and a control group based on body weight. Three days prior to the experiment, the rats underwent acclimation training. On the day of the experiment, the vehicle or drug was injected intraperitoneally. Sixty minutes later, tacrine was injected intraperitoneally at 5 mg / kg (body weight). After drug administration, the rats were placed in a transparent observation box. Ten minutes after administration, jaw tremor counts were performed, and the number of jaw tremors was recorded continuously for 5 minutes.

[0605] 6.3 Data processing and statistics

[0606] Experimental data It indicates that the inhibition rate %=100%*(number of jaw tremors in model group rats-number of jaw tremors in drug-treated group rats) / number of jaw tremors in model group rats, where *: p<0.05, **: p<0.01, ***: p<0.001 vs. vehicle.

[0607] 6.4 Experimental results: See Figure 1 (improvement of Tacrine-induced jaw tremor in rats by the compounds of the present invention at different concentrations).

[0608] 6.5 Experimental Conclusion

[0609] The free bases of Examples 28, 32, and 33 were tested in a Tacrine-induced rat jaw tremor model, using the anti-Parkinson's drug rotigotine as a positive control to investigate their potential anti-Parkinson's tremor effects. The results, as shown in Figures 1-3, show that compared with the model group, the positive control rotigotine (10 mg / kg), Example 28 (1 mg / kg, 3 mg / kg, 10 mg / kg), Example 32 (1 mg / kg, 3 mg / kg, 10 mg / kg), and Example 33 (1 mg / kg, 3 mg / kg, 10 mg / kg) significantly inhibited Tacrine-induced rat jaw tremor. The minimum effective doses of Examples 28, 32, and 33 were lower than those of the positive control. These results suggest that the compounds of the present invention have the potential to improve Parkinson's tremor symptoms.

[0610] Although the specific embodiments of the present invention have been described in detail, based on all the teachings disclosed, those skilled in the art may make various modifications and substitutions to the details of the technical solution of the present invention, and such modifications are within the scope of protection of the present invention. The full scope of the present invention is given by the appended claims and any equivalents thereof.

Claims

1. A compound represented by general formula (I), its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof, in: X is selected from amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group containing 1-4 heteroatoms selected from N, O or S, C 6-10 Aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, C 6-10 Aryl C 3-8 Cycloalkyl, C 6-10 an aromatic group and a 3- to 8-membered heterocyclic group containing 1 to 4 heteroatoms selected from N, O or S, a C 6-10 aryl and a 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, a 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S and C 3-8 Cycloalkyl or a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O or S and a 3- to 8-membered heterocyclyl group containing 1 to 4 heteroatoms selected from N, O or S, optionally further substituted by one or more R; R is selected from deuterium, halogen, hydroxyl, amino, thiol, nitro, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 The haloalkoxy group is optionally further selected from deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 substituted by one or more substituents in a haloalkoxy group; Z is selected from a bond, -(CR aa R bb ) m -, -C(O)(CR aa R bb ) m -, -O(CR aa R bb ) m -, -(CR aa R bb ) m O-, -(CR aa R bb ) m N(R cc )-, -S(O)(CR aa R bb ) m -, -S(O)2(CR aa R bb ) m -, -C(O)(CR aa R bb ) m N(R cc )-, -C(S)(CR aa R bb ) m N(R cc )- or -C(S)(CR aa R bb ) m -; M1 and M2 are each independently selected from CR aa , N, O or S; R aa and R bb are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, thiol, nitro, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 The haloalkoxy group is optionally further selected from deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 substituted by one or more substituents in a haloalkoxy group; R cc Selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 The haloalkoxy group is optionally further selected from deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 substituted by one or more substituents in a haloalkoxy group; R1 is selected from hydrogen, deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 The haloalkoxy group is optionally further selected from deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 substituted by one or more substituents in a haloalkoxy group; R2 is selected from hydroxyl, amino, thiol, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy; n is selected from 0, 1, 2, 3 or 4; m is selected from 0, 1, 2, 3, 4, 5 or 6.

2. The compound according to claim 1, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, wherein: It meets one or more of the following conditions: (1) Selected from the following groups: Preferred (2) X is selected from amino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group containing 1-4 heteroatoms selected from N, O or S, C 6-10 Aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, or C 6-10 aryl and a 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, optionally further substituted by one or more R, preferably amino, C 4-6 Cycloalkyl, 4-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, C 6-10 Aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, optionally further substituted with one or more R, more preferably X is selected from the following groups: wherein o is selected from 0, 1, 2, 3, 4 or 5; (3) R is selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy, preferably hydrogen, deuterium, halogen, cyano or C 1-6 Alkyl, more preferably hydrogen, deuterium, fluorine, chlorine, bromine, cyano or C 1-3 Alkyl, further preferably hydrogen, deuterium, fluorine, chlorine, cyano or methyl; (4) Z is selected from a bond, -(CH2) m -、-C(O)-、-C(O)(CH2) m -、-S(O)2-、-S(O)2(CH2) m or -C(O)N(CH3)-, preferably a bond, -C(O)-, -S(O)2- or -C(O)N(CH3)-; (5) R1 is selected from hydrogen, deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 Alkoxy, preferably hydrogen, deuterium or C 1-6 Alkyl, more preferably hydrogen, deuterium or C 1-3 Alkyl, further preferably hydrogen, deuterium, methyl, ethyl or propyl; (6) R2 is selected from hydroxyl, amino, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably hydroxy, amino, C 1-3 Alkyl or C 1-3 A haloalkyl group, more preferably a hydroxyl group or an amino group, further preferably an amino group; (7) n is selected from 0, 1, 2 or 3, preferably 0, 1 or 2; (8) m is selected from 0, 1, 2 or 3, preferably 0 or 1.

3. The compound according to claim 1 or 2, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, wherein: The general formula (I) further has the structure shown in the general formula (III): in: X, Z, R1 and n are as defined in claim 1 or 2.

4. The compound according to claim 3, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, wherein: The general formula (I) further has the structure shown by the general formula (III): in: Ring A is selected from C 6-10 Aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, or C 6-10 aryl and a 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, preferably C 6-10 Aryl or benzo containing 1 to 3 heteroatoms selected from N, O or S 5-6 membered heteroaryl, more preferably phenyl or benzothiophenyl; R is selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy, preferably hydrogen, deuterium, halogen, cyano or C 1-6 Alkyl, more preferably hydrogen, deuterium, fluorine, chlorine, bromine, cyano or C 1-3 Alkyl, further preferably hydrogen, deuterium, fluorine, chlorine, cyano or methyl; o is selected from 0, 1, 2 or 3, preferably 0, 1 or 2; R1 and n are as defined in claim 3.

5. The compound according to claim 4, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, wherein: In the general formula (III) Selected from the following groups: Preferred in: R3 and R4 are each independently selected from halogen, hydroxy, amino, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy, preferably halogen, cyano or C 1-6 The alkyl group is more preferably fluorine, chlorine or bromine, and further preferably chlorine.

6. The compound according to claim 3, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, wherein: The general formula (I) further has the structure shown in the general formula (IV): in: Xa is selected from amino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group containing 1-4 heteroatoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, optionally further substituted by one or more R a Substituted, preferably amino, C 4-6 Cycloalkyl, 4-6 membered heterocyclic group containing 1-3 heteroatoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, optionally further substituted by one or more R a More preferably, Xa is selected from the following groups: wherein y is selected from 0, 1, 2 or 3, preferably 0, 1 or 2; R a Selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy, preferably hydrogen, deuterium, halogen, cyano or C 1-6 Alkyl, more preferably hydrogen, deuterium, fluorine, chlorine, bromine, cyano or C 1-3 Alkyl, further preferably hydrogen, deuterium, fluorine, chlorine, cyano or methyl; n1 is selected from 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 1.

7. The compound according to claim 6, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, wherein: The Xa is selected from the following groups: Wherein: R5 and R6 are independently selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy, preferably halogen, cyano or C 1-6 Alkyl, more preferably fluorine, chlorine, bromine, cyano or C 1-3 The alkyl group is more preferably fluorine, chlorine, cyano or methyl.

8. The compound according to any one of claims 1 to 7, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, wherein: Selected from the following compounds:

9. A compound represented by general formula (V), its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof, in: n1 is selected from 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 1.

10. A method for preparing the compound according to claim 6, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, characterized in that: The steps include: The compound of general formula (V) undergoes a condensation reaction with a substituted carboxylic acid or an acid chloride to obtain a compound of general formula (IV), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof; Wherein: n1 and Xa are as described in claim 6.

11. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 8, its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof, and at least one pharmaceutical excipient selected from pharmaceutically acceptable carriers, diluents or excipients.

12. Use of the compound according to any one of claims 1 to 8, its stereoisomer, its tautomer or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 11 in the preparation of drugs involving or regulating 5-hydroxytryptamine receptors and / or dopamine receptors, preferably in the preparation of drugs involving or regulating 5-HT 1A receptors, dopamine D2 receptors and / or dopamine D3 receptor drugs.

13. Use of the compound according to any one of claims 1 to 8, its stereoisomer, its tautomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 11 in the preparation of a medicament for treating central nervous system diseases.

14. The method of claim 13, wherein the central nervous system disease is selected from one or more of Parkinson's disease, schizophrenia, bipolar disorder, depression, anxiety, mania, Huntington's disease, Alzheimer's disease, senile dementia, Alzheimer's type dementia, memory impairment, loss of executive function, vascular dementia, neuropathic pain, and functional disorders associated with intelligence, learning or memory, glaucoma, age-related macular degeneration, optic neuritis, ischemic disorder, and retinal edema, preferably Parkinson's disease.

Images